Researchers Database

OGURA Yasunori

FacultyFaculty Division of Human Life and Environmental Sciences Research Group of Food Science and Nutrition
Last Updated :2023/10/03


Profile and Settings

  • Name (Japanese)

  • Name (Kana)


Research Areas

  • Life sciences, Immunology
  • Life sciences, Bacteriology
  • Life sciences, Cell biology
  • Life sciences, Molecular biology

Research Experience

  • 2008, 2011, 琉球大学大学院医学研究科病原細菌学分野 助教
  • 2011, 奈良女子大学生活環境学部食物栄養学科 教授
  • 2004, 2008, Section of Immunobiology, School of Medicine, Yale University Research fellow
  • 1999, 2004, Department of Pathology, Medical school, University of Michigan Research fellow
  • 1998, 2002, 徳島大学分子酵素学研究センター分子細胞学部門 助手


  • 1994, 1998, Kyoto University, Graduate School, Division of Medicine, 分子医学系専攻
  • 1986, 1993, Kanazawa University, Faculty of Medicine, 医学科

Association Memberships

  • 日本発生生物学会
  • 日本免疫学会
  • American Association for the Advancement of Science
  • 日本細菌学会
  • 日本家政学会
  • 日本栄養改善学会


Published Papers

  • Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, PI3K/AKT/PTEN pathway as a target for Crohn's disease therapy, Nana Tokuhira; Yasuko Kitagishi; Miho Suzuki; Akari Minami; Atsuko Nakanishi; Yuna Ono; Keiko Kobayashi; Satoru Matsuda; Yasunori Ogura, The pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease, is a subject of increasing interest. Loss-of-function mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are strong genetic factors linked to Crohn's disease, which eventually leads to an excessive mucosal inflammatory response directed against components of normal gut microbiota. Reactive oxygen species (ROS) play an important role in inflammation processes, as well as in transduction of signals from receptors for several cytokines, such as tumor necrosis factor (TNF). ROS activate nuclear factor-B (NF-B) via IB kinase (IKK) through the PI3K/AKT/PTEN pathway. Therefore, this pathway is recognized to play a key role in Crohn's disease. Loss of function has been demonstrated to occur as an early event in a wide variety of diseases. Given this prevalent involvement in a number of diseases, the molecular development that modulates this pathway has been the subject of several studies. In addition, it has been the focus of extensive research and drug discovery activities. A better understanding of the molecular assemblies may reveal novel targets for the therapeutic development against Crohn's disease., Jan. 2015, 35, 1, 10, 16, Scientific journal, 10.3892/ijmm.2014.1981
  • Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Function of alpha-synuclein and PINK1 in Lewy body dementia, Akari Minami; Atsuko Nakanishi; Satoru Matsuda; Yasuko Kitagishi; Yasunori Ogura, alpha-synuclein (-syn) is the major protein component of Lewy bodies, a key pathological characteristic of the degenerating brain. The misfolding and aggregation of -syn is associated with both the idiopathic and familial forms of Parkinson's disease (PD) and Lewy body dementia (LBD). However, the function of -syn is poorly understood, as it shows both neurotoxic and neuroprotective activities. Mutations in phosphatase and tensin homologue-induced putative kinase 1 (PINK1) also cause recessively inherited PD. Studies support the notion of neuroprotective roles for PINK1, as it protects cells from damage-induced mitochondrial dysfunction, oxidative stress and cell apoptosis. PINK1 plays an essential role in mitochondrial quality control and its homeostasis is maintained through mitochondrial stabilization. The -syn aggregation is linked to various aspects of mitochondrial dysfunction and PINK1-related mitophagy. Determination of the molecular pathways that lead to -syn oligomerization and further aggregation may be the basis for the successful design and development of treatments for these neurodegenerative diseases. The present review summarizes the function of PINK1 underlying -syn aggregation and the mechanisms through which mitochondrial dysfunction plays a role in this process., Jan. 2015, 35, 1, 3, 9, Scientific journal, 10.3892/ijmm.2014.1980
  • Refereed, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, MDPI AG, Neuron Membrane Trafficking and Protein Kinases Involved in Autism and ADHD, Yasuko Kitagishi; Akari Minami; Atsuko Nakanishi; Yasunori Ogura; Satoru Matsuda, A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention., Feb. 2015, 16, 2, 3095, 3115, 10.3390/ijms16023095
  • Refereed, INTERNATIONAL JOURNAL OF ONCOLOGY, SPANDIDOS PUBL LTD, The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review), Atsuko Nakanishi; Yasuko Kitagishi; Yasunori Ogura; Satoru Matsuda, Numerous hereditary syndromes caused by mutations in multiple tumor suppressor genes can cause cancers. Germ line mutations in PTEN and p53 tumor suppressor cause Cowden syndrome and Li-Fraumeni syndrome, respectively. There exists some phenotypic overlap in these syndromes, and they are associated with high risks of breast cancer. The tumor suppressor protein PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream targets. PTEN gene is recognized as one of the most frequently mutated or mutated in many human cancers. Li-Fraumeni syndrome results from germline mutations of the tumor suppressor p53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. The p53 protein cooperates with PTEN and might be an essential blockage in development of mammary tumors. Many findings have demonstrated that PTEN as well as p53 plays a critical role in DNA damage response. This review summarizes the function of PTEN and p53 in carcinogenic cell signaling. In addition, we will discuss the role of PTEN signaling through its interaction with p53 and MDM2 pathways for the potential implications in hereditary cancer prevention and therapeutic intervention., Jun. 2014, 44, 6, 1813, 1819, 10.3892/ijo.2014.2377
  • Refereed, ALZHEIMERS RESEARCH & THERAPY, BIOMED CENTRAL LTD, Dietary regulation of PI3K/AKT/GSK-3 beta pathway in Alzheimer's disease, Yasuko Kitagishi; Atsuko Nakanishi; Yasunori Ogura; Satoru Matsuda, Alzheimer's disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3 beta pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3 beta pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD., 2014, 6, 3, 35, 10.1186/alzrt265
  • Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Atherosclerosis and tumor suppressor molecules (Review), Miho Suzuki; Aicari Minami; Atsuko Nakanishi; Keiko Kobayashi; Satoru Matsuda; Yasunori Ogura; Yasuko Kitagishi, Atherosclerosis, the major cause of heart attack and stroke, is a chronic inflammatory disease characterized by the formation of atherosclerotic plaque. Oxidized low-density lipoprotein through increased oxidative stress has been identified as one of the primary factors responsible for atherogenesis. Cell proliferation and death are key processes in the progression of atherosclerosis. The oxidative environment in areas of lipid accumulation is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage and levels of DNA repair are reduced during dietary lipid lowering. The tumor suppressor molecules play a pivotal role in regulating cell proliferation, DNA repair and cell death, which are important processes in regulating the composition of atherosclerotic plaque. Accordingly, in this review, we discuss the fundamental role of tumor suppressor molecules in regulating atherogenesis. In particular, we discuss how tumor suppressor molecules are activated in the complex environment of atherosclerotic plaque, and regulate growth arrest, cell senescence and the apoptosis of vascular smooth muscle cells, which may protect against the progression of atherosclerosis. In addition, we discuss promising alternatives to the use of medications (such as statin) against atherosclerosis, namely diet, with the use of plant-derived supplements to modulate the expression and/or activity of tumor suppressor molecules. We also summarize the progress of research made on herbs with a focus on the modulatory roles of tumor suppressors, and on the molecular mechanisms underlying the prevention if atherosclerosis, supporting designs for further research in this field., Oct. 2014, 34, 4, 934, 940, Scientific journal, 10.3892/ijmm.2014.1866
  • Refereed, Open Biochem J, Certain Diet and Lifestyle May Contribute to Islet β-cells Protection in Type-2 Diabetes via the Modulation of Cellular PI3K/AKT Pathway., OGURA Yasunori; Kitagishi Y; Nakanishi A; Minami A; Asai Y; Yasui M; Iwaizako A; Suzuki M; Ono Y; Ogura Y; Matsuda S, 2014, 8, 74-82
  • Refereed, Frontiers in Oncology, Frontiers Media S.A., Connection between tumor suppressor BRCA1 and PTEN in damaged DNA repair, Akari Minami; Atsuko Nakanishi; Yasunori Ogura; Yasuko Kitagishi; Satoru Matsuda, Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling., 2014, 4, 318, 10.3389/fonc.2014.00318
  • The Journal of Immunology, The American Association of Immunologists, Cutting Edge: Crohn’s Disease-Associated Nod2 Mutation Limits Production of Proinflammatory Cytokines To Protect the Host from Enterococcus faecalis-Induced Lethality, Yun-Gi Kim; Michael H. Shaw; Neil Warner; Jong-Hwan Park; Felicia Chen; Yasunori Ogura; Gabriel Núñez, 15 Sep. 2011, 187, 6, 2849, 2852, Scientific journal, 10.4049/jimmunol.1001854
  • Refereed, JOURNAL OF IMMUNOLOGY, AMER ASSOC IMMUNOLOGISTS, Cutting Edge: Crohn's Disease-Associated Nod2 Mutation Limits Production of Proinflammatory Cytokines To Protect the Host from Enterococcus faecalis-Induced Lethality, Yun-Gi Kim; Michael H. Shaw; Neil Warner; Jong-Hwan Park; Felicia Chen; Yasunori Ogura; Gabriel Nunez, Nucleotide-binding oligomerization domain 2 (Nod2) mutations including L1007fsinsC are associated with the development of Crohn's disease (CD). These CD-associated Nod2 mutations are common in healthy white populations, suggesting that they may confer some protective function, but experimental evidence is lacking. Using a mouse strain that expresses Nod2(2939iCstop), the equivalent of the L1007fsinsC mutation, we found that macrophages homozygous for Nod2(2939iCstop) are impaired in the recognition of muramyl dipeptide and Enterococcus faecalis, a commensal bacterium that is a common cause of sepsis-associated lethality in humans. Notably, Nod2 deficiency and homozygocity for Nod2(2939iCstop) were associated with reduced production of TNF-alpha and IL-6 and lethality after systemic infection with E. faecalis despite normal bacteria loads. Consistently, inhibition of TNF-alpha signaling protected wild-type mice from E. faecalis-induced lethality. These results suggest that the same Nod2 mutation can increase the susceptibility to CD, but also protect the host from systemic infection by a common enteric bacterium. The Journal of Immunology, 2011, 187: 2849-2852., Sep. 2011, 187, 6, 2849, 2852, Scientific journal, 10.4049/jimmunol.1001854
  • Refereed, FEMS Microbiology Letters, Oxford University Press (OUP), Detergents enhance EspB secretion from Escherichia coli strains harboring the locus for the enterocyte effacement (LEE) gene, Noboru Nakasone; Claudia Toma; Naomi Higa; Yukiko Koizumi; Yasunori Ogura; Toshihiko Suzuki, The effects of detergents (cholic acid, deoxycholic acid, Triton X-100, and Nonidet P-40) on the secretion of EspB from the locus for enterocyte effacement (LEE) gene-positive Escherichia coli strains were examined. Clinical isolates of eight EPEC strains and seven STEC strains were used to detect EspB after they had been cultivated in Luria-Bertani (LB) broth containing one of the detergents. When the bacteria were cultured in LB broth supplemented with one of the detergents, the amount of EspB produced was increased by 2-32-fold depending on the detergent and the strain used. EspB was detected in all strains when they were cultured in LB broth containing all of the detergents. The results obtained in this study can be applied to immunological diagnostic methods for detecting EspB and also to the production of EspB for research purposes., Feb. 2011, 315, 2, 109, 114, Scientific journal, 10.1111/j.1574-6968.2010.02176.x
  • Refereed, The Journal of Immunology, The American Association of Immunologists, Pathogenic Vibrio Activate NLRP3 Inflammasome via Cytotoxins and TLR/Nucleotide-Binding Oligomerization Domain-Mediated NF-κB Signaling, Claudia Toma; Naomi Higa; Yukiko Koizumi; Noboru Nakasone; Yasunori Ogura; Andrea J. McCoy; Luigi Franchi; Satoshi Uematsu; Junji Sagara; Shun’ichiro Taniguchi; Hiroko Tsutsui; Shizuo Akira; Jürg Tschopp; Gabriel Núñez; Toshihiko Suzuki, Vibrio vulnificus and Vibrio cholerae are Gram-negative pathogens that cause serious infectious disease in humans. The beta form of pro-IL-1 is thought to be involved in inflammatory responses and disease development during infection with these pathogens, but the mechanism of beta form of pro-IL-1 production remains poorly defined. In this study, we demonstrate that infection of mouse macrophages with two pathogenic Vibrio triggers the activation of caspase-1 via the NLRP3 inflammasome. Activation of the NLRP3 inflammasome was mediated by hemolysins and multifunctional repeat-in-toxins produced by the pathogenic bacteria. NLRP3 activation in response to V vulnificus infection required NF-kappa B activation, which was mediated via TLR signaling. V. cholerae-induced NLRP3 activation also required NF-kappa B activation but was independent of TLR stimulation. Studies with purified V cholerae hemolysin revealed that toxin-stimulated NLRP3 activation was induced by TLR and nucleotide-binding oligomerization domain 1/2 ligand-mediated NF-kappa B activation. Our results identify the NLRP3 inflammasome as a sensor of Vibrio infections through the action of bacterial cytotoxins and differential activation of innate signaling pathways acting upstream of NF-kappa B. The Journal of Immunology, 2010, 184: 5287-5297., 01 May 2010, 184, 9, 5287, 5297, Scientific journal, 10.4049/jimmunol.0903536
  • Refereed, JOURNAL OF EXPERIMENTAL MEDICINE, ROCKEFELLER UNIV PRESS, Inflammasome recognition of influenza virus is essential for adaptive immune responses, Takeshi Ichinohe; Heung Kyu Lee; Yasunori Ogura; Richard Flavell; Akiko Iwasaki, Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus., Jan. 2009, 206, 1, 79, 87, Scientific journal, 10.1084/jem.20081667
  • Refereed, IMMUNITY, CELL PRESS, The NLR gene family: A standard nomenclature, Jenny P. -Y. Ting; Ruth C. Lovering; Emad S. Alnemri; John Bertin; Jeremy M. Boss; Beckley K. Davis; Richard A. Flavell; Stephen E. Girardin; Adam Godzik; Jonathan A. Harton; Hal M. Hoffman; Jean-Pierre Hugot; Naohiro Inohara; Alex MacKenzie; Lois J. Maltais; Gabriel Nunez; Yasunori Ogura; Luc A. Otten; Dana Philpott; John C. Reed; Walter Reith; Stefan Schreiber; Viktor Steimle; Peter A. Ward, Mar. 2008, 28, 3, 285, 287, 10.1016/j.immuni.2008.02.005
  • Refereed, CELLULAR MICROBIOLOGY, WILEY, Maturation modulates caspase-1-independent responses of dendritic cells to Anthrax Lethal Toxin, Nuria Reig; Aimin Jiang; Rachael Couture; Fayyaz S. Sutterwala; Yasunori Ogura; Richard A. Flavell; Ira Mellman; F. Gisou van der Goot, Anthrax lethal toxin (LT) contributes to the immune evasion strategy of Bacillus anthracis by impairing the function of cells of the immune system, such as macrophages and dendritic cells (DCs). Macrophages from certain inbred mice strains undergo rapid death upon LT treatment mediated by caspase-1 activation dependent on Nalp1b, an inflammasome component. Rapid LT-induced death is however, not observed in macrophages from human and many mouse strains. Here, we focused on the responses of various murine DCs to LT. Using a variety of knockout mice, we found that depending on the mouse strain, death of bone marrow-derived DCs and macrophages was mediated either by a fast Nalp1b and caspase-1-dependent, or by a slow caspase-1-independent pathway that was triggered by the impairment of MEK1/2 pathways. Caspase-1-independent death was observed in cells of different genetic backgrounds and interestingly occurred only in immature DCs. Maturation, triggered by different types of stimuli, led to full protection of DCs. These studies illustrate that the cellular damage inflicted by LT depends not only on the innate responses but also on the maturation stage of the cell, which modulates the more general caspase-1-independent responses., May 2008, 10, 5, 1190, 1207, Scientific journal, 10.1111/j.1462-5822.2008.01121.x
  • Refereed, JOURNAL OF EXPERIMENTAL MEDICINE, ROCKEFELLER UNIV PRESS, Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome, Fayyaz S. Sutterwala; Lilia A. Mijares; Li Li; Yasunori Ogura; Barbara I. Kazmierczak; Richard A. Flavell, Pseudomonas aeruyinosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa-induced cell death and release of the proinflarnmatory cytokine interleukin (IL)-1 beta. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1-driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response., Dec. 2007, 204, 13, 3235, 3245, Scientific journal
  • Refereed, JOURNAL OF IMMUNOLOGY, AMER ASSOC IMMUNOLOGISTS, ASC/PYCARD and caspase-1 regulate the IL-18/IFN-gamma axis during Anaplasma phagocytophilum infection, Joao H. F. Pedra; Fayyaz S. Sutterwala; Bindu Sukumaran; Yasunori Ogura; Feng Qian; Ruth R. Montgomery; Richard A. Flavell; Erol Fikrig, Anaplasma phagocytophilum is an obligate intracellular pathogen that resides within nentrophils and can cause fever, pancytopenia, or death. IFN-gamma plays a critical role in the control of A. phagocytophilum; however, the mechanisms that regulate IFN-gamma production remain unclear. In this study, we demonstrate that apoptotic specklike protein with a caspase-activating recruiting domain (ASC)/PYCARD, a central adaptor molecule in the Nod-like receptor (NLR) pathway, regulates the IL-18/IFN-gamma axis during A. phagocytophilum infection through its effect on caspase-1. Caspase-1- and ase-null mice were more susceptible than control animals to A. phagocytophilum infection due to the absence of IL-18 secretion and reduced IFN-gamma levels in the peripheral blood. Moreover, caspase-1 and ASC deficiency reduced CD4(+) T cell-mediated IFN-gamma after in vitro restimulation with A. phagocytophilum. The NLR family member IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN-gamma production in response to A. phagocytophilum. Taken together, our data demonstrate that ASC and caspase-1 are critical for IFN-gamma-mediated control of A. phagocytophilum infection., Oct. 2007, 179, 7, 4783, 4791, Scientific journal
  • Refereed, JOURNAL OF LEUKOCYTE BIOLOGY, FEDERATION AMER SOC EXP BIOL, MDP-induced interleukin-1 beta processing requires Nod2 and CIAS1/NALP3, Qilin Pan; John Mathison; Colleen Fearns; Vladimir V. Kravchenko; Jean Da Silva Correia; Hal M. Hoffman; Koichi S. Kobayashi; John Bertin; Ethan P. Grant; Anthony J. Coyle; Fayyaz S. Sutterwala; Yasunori Ogura; Richard A. Flavell; Richard J. Ulevitch, Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (AIDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold-induced autoinflammatory syndrome I (CIAS1)/NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1 beta, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that AIDP-induced IL-1 beta release requires Nod2 and CIASI/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. In contrast, AIDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-I beta production and allow for further studies of the role of these proteins within the broader context of inflammatory disease., Jul. 2007, 82, 1, 177, 183, Scientific journal, 10.1189/jlb.1006627
  • Refereed, JOURNAL OF LEUKOCYTE BIOLOGY, FEDERATION AMER SOC EXP BIOL, The inflammasome in pathogen recognition and inflammation, Fayyaz S. Sutterwala; Yasunori Ogura; Richard A. Flavell, The nucleotide-binding oligomerization domain-like receptor (NLR) family of proteins is involved in the regulation of innate immune responses and cell death pathways. Some NLR family members promote the activation of proinflammatory caspases within multiprotein complexes, called inflammasomes. Recent studies analyzing mice deficient in various components of the inflammasome have provided insight into the role of these molecules in host defense against pathogens and in autoinflammatory disorders. Here, we review these studies and propose that membrane disruption leads to activation of the inflammasome., Aug. 2007, 82, 2, 259, 264, 10.1189/jlb.1206755
  • Refereed, JOURNAL OF EXPERIMENTAL MEDICINE, ROCKEFELLER UNIV PRESS, Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis, Maria Lara-Tejero; Fayyaz S. Sutterwala; Yasunori Ogura; Ethan P. Grant; John Bertin; Anthony J. Coyle; Richard A. Flavell; Jorge E. Galan, Caspase-1 is activated by a variety of stimuli after the assembly of the "inflammasome," an activating platform made up of a complex of the NOD-LRR family of proteins. Caspase-1 is required for the secretion of proinflammatory cytokines, such as interleukin ( IL)-1 beta and IL-18, and is involved in the control of many bacterial infections. Paradoxically, however, its absence has been reported to confer resistance to oral infection by Salmonella typhimurium. We show here that absence of caspase-1 or components of the inflammasome does not result in resistance to oral infection by S. typhimurium, but rather, leads to increased susceptibility to infection., Jun. 2006, 203, 6, 1407, 1412, Scientific journal, 10.1084/jem.20060206
  • Refereed, IMMUNITY, CELL PRESS, Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1, FS Sutterwala; Y Ogura; M Szczepanik; M Lara-Tejero; GS Lichtenberger; EP Grant; J Berlin; AJ Coyle; JE Galan; PW Askenase; RA Flavell, Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1 beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1 alpha, IL-1 beta, and IL-18. IL-1 beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway., Mar. 2006, 24, 3, 317, 327, Scientific journal, 10.1016/j.immuni.2006.02.004
  • Refereed, NATURE IMMUNOLOGY, NATURE PUBLISHING GROUP, The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection, DS Zamboni; KS Kobayashi; T Kohlsdorf; Y Ogura; EM Long; RE Vance; K Kuida; S Mariathasan; VM Dixit; RA Flavell; WF Dietrich; CR Roy, Baculovirus inhibitor of apoptosis repeat-containing 1 (Birc1) proteins have homology to several germline-encoded receptors of the innate immune system. However, their function in immune surveillance is not clear. Here we describe a Birc1e-dependent signaling pathway that restricted replication of the intracellular pathogen Legionella pneumophila in mouse macrophages. Translocation of bacterial products into host-cell cytosol was essential for Birc1e-mediated control of bacterial replication. Caspase-1 was required for Birc1e-dependent antibacterial responses ex vivo in macrophages and in a mouse model of Legionnaires' disease. The interleukin 1 beta converting enzyme-protease-activating factor was necessary for L. pneumophila growth restriction, but interleukin 1 beta was not required. These results establish Birc1e as a nucleotide-binding oligomerization-leucine-rich repeat protein involved in the detection and control of intracellular L. pneumophila., Mar. 2006, 7, 3, 318, 325, Scientific journal, 10.1038/ni1305
  • Refereed, JOURNAL OF ENDOTOXIN RESEARCH, MANEY PUBLISHING, NALP3: a key player in caspase-1 activation, Fayyaz S. Sutterwala; Yasunori Ogura; Dario S. Zamboni; Craig R. Roy; Richard A. Flavell, The NLR (NACHT-LRR) family of proteins have been implicated in the regulation of immune responses and cell death pathways. Some NLR family members can form multiprotein complexes, called inflammasomes, involved in the activation of pro-inflammatory caspases. Mutations in the NALP3/CIAS1/cryopyrin gene, a member of the NLR family, are linked to three auto-inflammatory disorders: Muckle-Wells syndrome, familial cold auto-inflammatory syndrome and neonatal-onset multisystem inflammatory disease. NALP3 along with the adaptor molecule ASC activates caspase-1 in response to a wide variety of stimuli. Here we review recent findings on the biology of NALP3 suggesting that it has functions beyond that of pathogen recognition., 2006, 12, 4, 251, 256, Scientific journal, 10.1179/096805106X118771
  • Refereed, CELL, CELL PRESS, The inflammasome: First line of the immune response to cell stress, Yasunori Ogura; Fayyaz S. Sutterwala; Richard A. Flavell, Aug. 2006, 126, 4, 659, 662, 10.1016/j.cell.2006.08.002
  • Refereed, JOURNAL OF BIOLOGICAL CHEMISTRY, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, A role for Erbin in the regulation of Nod2-dependent NF-kappa B signaling, C McDonald; FF Chen; Ollendorff, V; Y Ogura; S Marchetto; P Lecine; JP Borg; G Nunez, Nod2 is an intracellular sensor of a specific bacterial cell wall component, muramyl dipeptide, and activation of Nod2 stimulates an inflammatory response. Specific mutations of Nod2 have been associated with two inflammatory diseases, Crohn disease and Blau syndrome, and are thought to contribute to disease susceptibility through altering Nod2 signaling. Association of disease with inappropriate activation of Nod2 highlights the importance of proper regulation of Nod2 activity. However, little is known about specific regulation of the Nod2 pathway. We performed a biochemical screen to discover potential regulators of Nod2 and identified Erbin, a protein involved in cell polarity, receptor localization, and regulation of the mitogen-activated protein kinase pathway, as a novel Nod2-interacting protein. In our studies, we demonstrate specific interaction of Erbin and Nod2 both in vitro and in vivo and characterize the regions required for interaction in both proteins. We found that Nod2-dependent activation of NF-kappa B and cytokine secretion is inhibited by Erbin overexpression, whereas Erbin(-/-) mouse embryo fibroblasts show an increased sensitivity to muramyl dipeptide. These studies identify Erbin as a regulator of Nod2 signaling and demonstrate a novel role for Erbin in inflammatory responses., Dec. 2005, 280, 48, 40301, 40309, Scientific journal, 10.1074/jbc.M508538200
  • Refereed, SCIENCE, AMER ASSOC ADVANCEMENT SCIENCE, Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract, KS Kobayashi; M Chamaillard; Y Ogura; O Henegariu; N Inohara; G Nunez; RA Flavell, The gene encoding the Nod2 protein is frequently mutated in Crohn's disease (CD) patients, although the physiological function of Nod2 in the intestine remains elusive. Here we show that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. These animals are susceptible to bacterial infection via the oral route but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal anti-microbial peptides, known as cryptdins. The Nod2 protein is thus a critical regulator of bacterial immunity within the intestine, providing a possible mechanism for Nod2 mutations in CD., Feb. 2005, 307, 5710, 731, 734, Scientific journal, 10.1126/science.1104911
  • Refereed, EMBO JOURNAL, NATURE PUBLISHING GROUP, Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition, T Tanabe; M Chamaillard; Y Ogura; L Zhu; S Qiu; J Masumoto; P Ghosh; A Moran; MM Predergast; G Tromp; CJ Williams; N Inohara; G Nunez, Multiple genetic variants of CARD15/NOD2 have been associated with susceptibility to Crohn's disease and Blau syndrome. NOD2 recognizes muramyl dipeptide (MDP) derived from bacterial peptidoglycan (PGN), but the molecular basis of recognition remains elusive. We performed systematic mutational analysis to gain insights into the function of NOD2 and molecular mechanisms of disease susceptibility. Using an archive of 519 mutations covering similar to50% of the amino-acid residues of NOD2, the essential regulatory domains and specific residues of NOD2 involved in recognition of MOP were identified. The analysis revealed distinct roles for N-terminal and C-terminal leucine-rich repeats (LRRs) in the modulation of NOD2 activation and bacterial recognition. Within the C-terminal LRRs, variable residues predicted to form the beta-strand/betaturn structure were found to be essential for the response to MDP. In addition, we analyzed NOD1, a NOD2-related protein, revealing conserved and nonconserved amino-acid residues involved in PGN recognition. These results provide new insights into the molecular function and regulation of NOD2 and related NOD family proteins., Apr. 2004, 23, 7, 1587, 1597, Scientific journal, 10.1038/sj.emboj.7600175
  • Refereed, GUT, B M J PUBLISHING GROUP, Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis, Y Ogura; S Lala; W Xin; E Smith; TA Dowds; FF Chen; E Zimmermann; M Tretiakova; JH Cho; J Hart; JK Greenson; S Keshav; G Nunez, Background and aims: Genetic variation in NOD2 has been associated with susceptibility to Crohn's disease (CD) and specifically with ileal involvement. The reason for the unique association of NOD2 mutations with ileal disease is unclear. To identify a possible link, we tested expression of NOD2 in intestinal tissue of CD patients and controls. Patients and methods: Fifty five specimens of ileum or colon from 21 CD patients, seven ulcerative colitis (UC) patients, and five controls with pathology other than CD or UC were stained for NOD2 using an immunoperoxidase method. Results: Using a monoclonal antibody against NOD2 developed in our laboratory, we detected uniform expression of NOD2 in terminal ileum Paneth cells from controls and patients as well as in metaplastic Paneth cells in the colon. Mechanical purification showed enriched expression of NOD2 mRNA in ileal crypts. In Paneth cells, NOD2 was located in the cytosol in close proximity to the granules that contain antimicrobial peptides. We detected minimal NOD2 in the villous epithelium of the ileum or in the colonic epithelium from both CD patients and controls. Conclusions: These results suggest a role for NOD2 in the regulation of Paneth cell mediated responses against intestinal bacteria and a plausible mechanism to explain the selective association of NOD2 mutations with ileal disease. The impaired capacity of CD associated mutations to sense luminal bacteria may result in increased susceptibility to certain gut microbes., Nov. 2003, 52, 11, 1591, 1597, Scientific journal
  • Refereed, GASTROENTEROLOGY, W B SAUNDERS CO-ELSEVIER INC, Crohn's disease and the NOD2 gene: A role for paneth cells, S Lala; Y Ogura; C Osborne; SY Hor; A Bromfield; S Davies; O Ogunbiyi; G Nunez; S Keshav, Background & Aims: The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LIPS), inducing cellular activation. However, the mechanisms by which NOD2 mutations cause terminal ileitis are unknown, and NOD2 is expressed most highly by peripheral blood monocytes, which are distributed ubiquitously and readily respond to LIPS via cell-surface receptors. Paneth cells on the other hand, are most numerous in the terminal ileum, are critically important in enteric antibacterial defense, and respond to LIPS through as yet undefined pathways. We therefore determined if these specialized intestinal epithelial cells also expressed the NOD2 gene. Methods: In situ hybridization, immunohistochemistry, and laser-capture microdissection were used to determine RNA and protein expression in tissue sections, and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to quantitate gene expression in intestinal epithelial cells and peripheral blood mononuclear cells. Results: NOD2 was detected readily in monocytes, but not in mature macrophages in the lamina propria or within granulomas, and levels declined as monocytes differentiated into macrophages in vitro, so that Caco-2 cells expressed more NOD2 mRNA than macrophages. NOD2 mRNA was enriched in crypts compared with villi, and in situ, Paneth cells were the most prominent cells expressing NOD2 in normal and CD-affected intestinal tissue, where they also strongly expressed tumor necrosis factor alpha (TNFalpha) RNA. Conclusions: The NOD2 gene product is most abundant in Paneth cells in the terminal ileum, which could therefore play a critical and hitherto unrecognized role in the pathogenesis of NOD2-associated CD., Jul. 2003, 125, 1, 47, 57, Scientific journal, 10.1016/S0016-5085(03)00661-9
  • Refereed, NATURE IMMUNOLOGY, NATURE PUBLISHING GROUP, An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid, M Chamaillard; M Hashimoto; Y Horie; J Masumoto; S Qiu; L Saab; Y Ogura; A Kawasaki; K Fukase; S Kusumoto; MA Valvano; SJ Foster; TW Mak; G Nunez; N Inohara, Nucleotide-binding oligomerization domain protein 1 (NOD1) belongs to a family that includes multiple members with NOD and leucine-rich repeats in vertebrates and plants. NOD1 has been suggested to have a role in innate immune responses, but the mechanism involved remains unknown. Here we report that NOD1 mediates the recognition of peptidoglycan derived primarily from Gram-negative bacteria. Biochemical and functional analyses using highly purified and synthetic compounds indicate that the core structure recognized by NOD1 is a dipeptide, gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP). Murine macrophages deficient in NOD1 did not secrete cytokines in response to synthetic iE-DAP and did not prime the lipopolysaccharide response. Thus, NOD1 mediates selective recognition of bacteria through detection of iE-DAP-containing peptidoglycan., Jul. 2003, 4, 7, 702, 707, Scientific journal
  • Refereed, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC ELSEVIER SCIENCE, ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis, J Masumoto; TA Dowds; P Schaner; FF Chen; Y Ogura; M Li; L Zhu; T Katsuyama; J Sagara; S Taniguchi; DL Gumucio; G Nunez; N Inohara, ASC is a pro-apoptotic protein containing a pyrin domain (PD) and a caspase-recruitment domain (CARD). A previous study suggests that ASC interacts with Ipaf, a member of the Apaf-l/Nodl protein family. However, the functional relevance of the interaction has not been determined. Here, we report that co-expression of ASC with Ipaf or oligomerization of ASC induces both apoptosis and NF-kappaB activation. Apoptosis induced through ASC was inhibited by a mutant form of Caspase-8 but not by that of Caspase-1. The PD of ASC physically interacted with Caspase-8 as well as with pyrin, the familial Mediterranean fever gene product. Caspase-8 deficiency rescued mouse fibroblasts from apoptosis induced by ASC oligomerization. Pyrin disrupted the interaction between ASC and Caspase-8, and inhibited both apoptosis and NF-kappaB activation induced by ASC. These findings suggest that ASC is a mediator of NF-kappaB activation and Caspase-8-dependent apoptosis in an Ipaf signaling pathway. (C) 2003 Elsevier Science (USA). All rights reserved., Mar. 2003, 303, 1, 69, 73, Scientific journal, 10.1016/S0006-291X(03)00309-7
  • Refereed, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC ELSEVIER SCIENCE, Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product, TA Dowds; J Masumoto; FF Chen; Y Ogura; N Inohara; G Nunez, Cryopyrin, a member of the Nod protein family mutated in familial cold urticaria and Muckle-Wells syndrome, has been recently implicated in inflammation. However, the mechanism of activation and regulation of the cryopyrin signaling pathway remains poorly understood. We report here that co-expression of cryopyrin with its binding partner, ASC, induced both apoptosis and NF-kappaB activation. This signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin activates downstream targets as reported for other Nod family members. Notably, pyrin, the product of the familial Mediterranean fever gene, inhibited cryopyrin-mediated apoptosis and NF-kappaB activation by disrupting the cryopyrin-ASC interaction. These results provide evidence for a cryopyrin signaling pathway activated through the induced proximity of ASC, which is negatively regulated by pyrin. (C) 2003 Elsevier Science (USA). All rights reserved., Mar. 2003, 302, 3, 575, 580, Scientific journal, 10.1016/S0006-291X(03)00221-3
  • Refereed, GENOMICS, ACADEMIC PRESS INC ELSEVIER SCIENCE, Genetic variation and activity of mouse Nod2, a susceptibility gene for Crohn's disease, Y Ogura; L Saab; FF Chen; A Benito; N Inohara; G Nunez, Genetic variation in human Nod2 has been associated with susceptibility to Crohn's disease. The mouse Nod2 locus is located at chromosome 8 and composed of 12 exons, 11 of which encode the Nod2 protein. Sequence analysis of Nod2 from 45 different strains of Mus musculus and Mus spretus revealed extensive polymorphism involving all exons of Nod2. Of the 140 polymorphic sites identified, 68 were located in the coding region, of which 28 created amino acid substitutions in Nod2. Expression of mouse Nod2 activated NF-kappaB and conferred responsiveness to bacterial components, an activity that was deficient in mutants corresponding to those associated with susceptibility to Crohn's disease. These studies demonstrate a conserved role for Nod2 in the response to bacterial components and suggest that selective evolutionary pressure exerted by pathogens may have contributed to the high level of variability of Nod2 sequences in both humans and mice. (C) 2003 Elsevier Science (USA). All rights reserved., Apr. 2003, 81, 4, 369, 377, Scientific journal, 10.1016/S0888-7543(03)00027-2
  • Refereed, GASTROENTEROLOGY, W B SAUNDERS CO, Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan, DK Bonen; Y Ogura; DL Nicolae; N Inohara; L Saab; T Tanabe; FF Chen; SJ Foster; RH Duerr; Brant, SR; JH Cho; G Nunez, Background & Aims: The NOD2 variants R702W, G908R, and L1007fsinsC are strongly associated with Crohn's disease (CD) in both European and American populations, but whether this susceptibility extends to all ethnic groups remains unknown. Except for the L1007fsinsC mutation, which produces a truncated NOD2 protein, the functional activity of the major CD-associated variants G908R and R702W is unknown. Methods: Individuals were genotyped for R702W, G908R, and L1007fsinsC. The ability of G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S to confer responsiveness to lipopolysaccharide (LPS) and peptidoglycan (PGN) was determined in HEK293T kidney cells. Results: G908R and L1007fsinsC, but not R702W, were associated with disease susceptibility in Ashkenazi Jews. Ashkenazi Jews with CD had significantly higher allele frequency carriage of G908R and lower carriage of R702W compared with non-Jewish whites with CD. Functional studies revealed that the G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S are defective in their ability to respond to bacterial LPS and PGN, whereas P268S alone exhibited wild-type activity. Conclusions: R702W is hot associated with susceptibility to CD in Ashkenazi Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect in response to bacterial components, providing evidence for a unifying molecular mechanism whereby NOD2 mutations contribute to disease susceptibility., Jan. 2003, 124, 1, 140, 146, Scientific journal, 10.1053/gast.2003.50019
  • Refereed, JOURNAL OF BIOLOGICAL CHEMISTRY, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation, O Gutierrez; C Pipaon; N Inohara; A Fontalba; Y Ogura; F Prosper; G Nunez; JL Fernandez-Luna, Nod2, a member of the Apaf1/Nod protein family, confers responsiveness to bacterial products and activates NF-kappaB, a transcription factor that plays a central role in innate immunity. Recently, genetic variation in Nod2 has been associated with susceptibility to Crohn's disease. Here, we report that expression of Nod2 is induced upon differentiation of CD34(+) hematopoietic progenitor cells into granulocyte or monocyte/macrophages. In peripheral blood cells, the highest levels of Nod2 were observed in CD14(+) (monocytes), CD15(+) (granulocytes), and CD40(+)/CD86(+) (dendritic cells) cell populations. Notably, stimulation of myeloblastic and epithelial cells with bacterial lipopolysaccharide or TNFalpha resulted in up-regulation of Nod2. A search for consensus sites within the Nod2 promoter revealed a NF-kappaB binding element that was required for transcriptional activity in response to TNFalpha. Moreover, ectopic expression of p65 induced transactivation, whereas that of dominant-negative IkappaBalpha blocked the transcriptional activity of the Nod2 promoter. Upon stimulation with TNFalpha or lipopolysaccharide, both p50 and p65 subunits of NF-kappaB were bound to the Nod2 promoter. Thus, Nod2 expression is enhanced by proinflammatory cytokines and bacterial components via NF-kappaB, a mechanism that may contribute to the amplification of the innate immune response and susceptibility to inflammatory disease., Nov. 2002, 277, 44, 41701, 41705, Scientific journal, 10.1074/jbc.M206473200
  • Refereed, GASTROENTEROLOGY, W B SAUNDERS CO, Lack of common NOD2 variants in Japanese patients with Crohn's disease, N Inoue; K Tamura; Y Kinouchi; Y Fukuda; S Takahashi; Y Ogura; N Inohara; G Nunez; Y Kishi; Y Koike; T Shimosegawa; T Shimoyama; T Hibi, Background & Aims: Previous studies have linked Crohn's disease (CD) to the pericentromeric region of chromosome 16 (IBD1). Three independent studies of Western populations have recently shown that 3 variants of NOD 2, a gene located at 16q12, are associated with susceptibility to CD. Here, we have evaluated the 3 NOD2 variants in Japanese patients to determine whether the gene is also associated with susceptibility to CD in a non-Western population. Methods: Blood samples were obtained from 350 patients with CD, 272 patients with ulcerative colitis, and 292 healthy controls at 3 hospitals in Japan. DNA was sequenced in the region of the 3 NOD2 variants (C2104T in exon 4, G2722C in exon 8, and 3020insC in exon 11) by genomic polymerase chain reaction followed by direct sequencing. Results: Among the subjects in our 3 study groups, including patients with CD, patients with ulcerative colitis, and healthy controls, none had common NOD2 variants that have been associated with CD in white patients. Conclusions: These results indicate that genetic variation, which may predispose some human populations to CD, may not be present in other populations and specifically that common variants in NOD2 found in white patients with CD are not associated with CD in the Japanese population., Jul. 2002, 123, 1, 86, 91, Scientific journal, 10.1053/gast.2002.34155
  • Refereed, CURRENT OPINION IN MICROBIOLOGY, CURRENT BIOLOGY LTD, Nods: a family of cytosolic proteins that regulate the host response to pathogens, N Inohara; Y Ogura; G Nunez, Genetic variation in Nod2 is associated with susceptibility to Crohn's disease. Nod2 and its homologue, Nod1, are members of a growing family of cytosolic factors related to the apoptosis regulator Apaf-1 and a class of plant disease resistance proteins. Nod1 and Nod2 confer responsiveness to lipopolysaccharicles and interact with RICK, a mediator of NF-kappaB activation. Nod1 and Nod2 and related Nods appear to regulate the host response to pathogens, a process that may be faulty in certain inflammatory diseases. Recent studies that suggest that Nods may be involved in the recognition of pathogen components in the cytosol of mammalian cells are reviewed., Feb. 2002, 5, 1, 76, 80
  • Refereed, Bio Clinica, 炎症性腸疾患と遺伝子異常, OGURA Yasunori, 2002, 1
  • Refereed, JOURNAL OF INVESTIGATIVE DERMATOLOGY, BLACKWELL PUBLISHING INC, Lack of association between NOD2 3020InsC frameshift mutation and psoriasis, RP Nair; P Stuart; Y Ogura; N Inohara; NVC Chia; L Young; T Henseler; S Jenisch; E Christophers; JJ Voorhees; G Nunez; JT Elder, Dec. 2001, 117, 6, 1671, 1672
  • Refereed, NATURE, MACMILLAN PUBLISHERS LTD, A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease, Y Ogura; DK Bonen; N Inohara; DL Nicolae; FF Chen; R Ramos; H Britton; T Moran; R Karaliuskas; RH Duerr; JP Achkar; Brant, SR; TM Bayless; BS Kirschner; SB Hanauer; G Nunez; JH Cho, Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies(1-6), but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease., May 2001, 411, 6837, 603, 606, Scientific journal
  • Refereed, JOURNAL OF BIOLOGICAL CHEMISTRY, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappa B, Y Ogura; N Inohara; A Benito; FF Chen; S Yamaoka; G Nunez, Apaf-1 and Nod1 are members of a protein family, each of which contains a caspase recruitment domain (CARD) linked to a nucleotide-binding domain, which regulate apoptosis and/or NF-kappaB activation. Nod2, a third member of the family, was identified. Nod2 is composed of two N-terminal CARDs, a nucleotide-binding domain, and multiple C-terminal leucine-rich repeats. Although Nod1 and Apaf-1 were broadly expressed in tissues, the expression of Nod2 was highly restricted to monocytes, Nod2 induced nuclear factor kappaB (NF-kappaB) activation, which required IKK gamma and was inhibited by dominant negative mutants of I kappaB alpha, IKK alpha, IKK beta, and IKK gamma. Nod2 interacted with the serine-threonine kinase RICK via a hemophilic CARD-CARD interaction. Furthermore, NF-kappaB activity induced by Nod2 correlated with its ability to interact with RICK and was specifically inhibited by a truncated mutant form of RICK containing its CARD. The identification of Nod2 defines a subfamily of Apaf-1-like proteins that function through RICK to activate a NF-kappaB signaling pathway., Feb. 2001, 276, 7, 4812, 4818, Scientific journal
  • Refereed, JOURNAL OF BIOLOGICAL CHEMISTRY, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Human Nod1 confers responsiveness to bacterial lipopolysaccharides, N Inohara; Y Ogura; FF Chen; A Muto; G Nunez, The immune response to microbial pathogens is initiated by recognition of specific pathogen components by host cells both at the cell surface and in the cytosol, While the response triggered by pathogen products at the surface of immune cells is well characterized, that initiated in the cytosol is poorly understood. Nod1 is a member of a growing family of intracellular proteins with structural homology to apoptosis regulators Apaf-1/Ced-4 and a class of plant disease-resistant gene products. Here we show that bacterial lipopolysaccharides, but not other pathogen components tested, induced TLR4- and MyD88-independent NF-kappaB activation in human embryonic kidney 293T cells expressing trace amounts of Nod1, Nod2, another Nod family member, also conferred responsiveness to bacterial components but with a response pattern different from that observed with Nod1. As it was reported for plant disease-resistant R proteins, the leucine-rich repeats of Nod1 and Nod2 were required for lipopolysaccharide-induced NF-kappaB activation. A lipopolysaccharide binding activity could be specifically coimmunopurified with Nod1 from cytosolic extracts. These observations suggest that Nod1 and Nod2 are mammalian counterparts of plant disease-resistant gene products that may function as cytosolic receptors for pathogen components derived from invading bacteria., Jan. 2001, 276, 4, 2551, 2554, Scientific journal
  • Refereed, 実験医学, クローン病感受性遺伝子IBD1/Nod2の同定, OGURA Yasunori, 2001, 8, 1542-1544
  • Refereed, JOURNAL OF BIOLOGICAL CHEMISTRY, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways, N Inohara; T Koseki; JM Lin; L del Peso; PC Lucas; FF Chen; Y Ogura; G Nunez, Nod1 is an Apaf-1-like molecule composed of a caspase-recruitment domain (CARD), nucleotide-binding domain, and leucine-rich repeats that associates with the CARD-containing kinase RICK and activates nuclear factor kappa B (NF-kappa B). We show that self-association of Nod1 mediates proximity of RICK and the interaction of RICK with the gamma subunit of the I kappa B kinase (IKK gamma). Similarly, the RICK-related kinase RIP associated via its intermediate region with IKK gamma, A mutant form of IKK gamma deficient in binding to IKK alpha and IKK beta inhibited NF-kappa B activation induced by RICK or RIP. Enforced oligomerization of RICK or RIP as well as of IKK gamma, IKK alpha, or IKK beta was sufficient for induction of NF-kappa B activation. Thus, the proximity of RICK, RIP, and IKK complexes may play an important role for NF-kappa B activation during Nod1 oligomerization or trimerization of the tumor necrosis factor alpha receptor., Sep. 2000, 275, 36, 27823, 27831, Scientific journal
  • Refereed, BIOLOGY OF REPRODUCTION, SOC STUDY REPRODUCTION, Essential role of platelet-derived growth factor receptor alpha in the development of the intraplacental yolk sac sinus of Duval in mouse placenta, Y Ogura; N Takakura; H Yoshida; S Nishikawa, Platelet-derived growth factor receptor alpha (PDCFR alpha) is expressed in multiple tissues and exerts its function throughout mouse embryogenesis. Upon screening the PDCFR alpha-expressing tissues in mouse embryos by immunohistochemistry using our established monoclonal antibody against murine PDGFRa, we found its expression in an epithelium lining a sinusoidal structure in placenta. This structure was proven to be the sinus of Duval, and the PDGFR alpha-positive epithelium to be the intraplacental yolk sac (IPY). The IPY has been postulated to be a derivative of primitive endoderm because of its morphology and its expression of vitamin D-dependent 9-kDa calcium-binding protein, and to play some roles in materno-fetal transport. In this study, we demonstrated that the IPY develops from primitive endoderm by its invagination into chorioallantoic placenta and continues to strongly express PDCFR alpha until the prenatal stage. Moreover, we found that the IPY is completely absent in Pdgfra(Ph)/Pdgfra(Ph) mutant embryos, which lack the Pdgfra gene, suggesting that the function of PDGFR alpha is essential to its formation. Hence, PDGFR alpha expressed in the IPY should be listed as a component of the cytokine network of murine placental development., Jan. 1998, 58, 1, 65, 72, Scientific journal
  • Refereed, JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, HISTOCHEMICAL SOC INC, PDGFR alpha expression during mouse embryogenesis: Immunolocalization analyzed by whole-mount immunohistostaining using the monoclonal anti-mouse PDGFR alpha antibody APA5, N Takakura; H Yoshida; Y Ogura; H Kataoka; S Nishikawa; SI Nishikawa, We investigated the cells that express platelet-derived growth factor receptor alpha (PDGFR alpha) during mouse embryogenesis. PDGFR alpha expression has been identified by in situ hybridization or immunohistochemistry using polyclonal antibodies on tissue sections. Because no immunostaining study using whole-mount specimens has been published to date, we established a new monoclonal antibody (MAb), APA5, for this purpose. Our results differed in that APA5 stained only the paraxial mesoderm, whereas other investigators concluded that most if not all mesodermal cells expressed PDGFR alpha. Moreover, we did not find PDGFR alpha expression in embryonic erythrocytes, which have been previously suggested to express PDGFR alpha. On the basis of our present results, we wish to revise the proposed PDGFR alpha expression as follows. At the pregastrulation stage, PDGFR alpha is expressed only in primitive endoderm, particularly that in the ectoplacental cone. On gastrulation, it is expressed at high levels in the paraxial mesoderm. This expression continues after its differentiation into the somite. Along with the differentiation and migration of the sclerotome, PDGFR alpha(+) cells begin to become distributed throughout the embryonal mesenchyme. During organogenesis, particularly intense staining is detected in regions of epithelial and mesenchymal interaction, such as the tooth bud and bronchi. In addition to mesodermal derivatives, the developing lens, apical ectodermal ridge, glial precursor, cardiac valves, and choroid plexus express PDGFR alpha. Our results with whole-mount immunostaining show that PDGFR alpha is abundantly expressed and may play important roles during embryogenesis., Jun. 1997, 45, 6, 883, 893, Scientific journal
  • Nature Communications, Springer Science and Business Media LLC, NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease, Hazel Tye; Chien-Hsiung Yu; Lisa A. Simms; Marcel R. de Zoete; Man Lyang Kim; Martha Zakrzewski; Jocelyn S. Penington; Cassandra R. Harapas; Fernando Souza-Fonseca-Guimaraes; Leesa F. Wockner; Adele Preaudet; Lisa A. Mielke; Stephen A. Wilcox; Yasunori Ogura; Sinead C. Corr; Komal Kanojia; Konstantinos A. Kouremenos; David P. De Souza; Malcolm J. McConville; Richard A. Flavell; Motti Gerlic; Benjamin T. Kile; Anthony T. Papenfuss; Tracy L. Putoczki; Graham L. Radford-Smith; Seth L. Masters, Dec. 2018, 9, 1, Scientific journal, 10.1038/s41467-018-06125-0
  • Microbiology and Immunology, Wiley, Effects ofPsidium guajavaleaf extract on secretion systems of gram-negative enteropathogenic bacteria, Noboru Nakasone; Yasunori Ogura; Naomi Higa; Claudia Toma; Yukiko Koizumi; Giichi Takaesu; Toshihiko Suzuki; Tetsu Yamashiro, Jul. 2018, 62, 7, 444, 453, Scientific journal, 10.1111/1348-0421.12604
  • FEMS Microbiology Letters, Oxford University Press (OUP), Epigallocatechin gallate inhibits the type III secretion system of Gram-negative enteropathogenic bacteria under model conditions, Noboru Nakasone; Naomi Higa; Claudia Toma; Yasunori Ogura; Toshihiko Suzuki; Tetsu Yamashiro, 15 Jul. 2017, 364, 13, Scientific journal, 10.1093/femsle/fnx111
  • FEMS Immunology & Medical Microbiology, Oxford University Press (OUP), Receptor interacting protein-2 contributes to host defense againstAnaplasma phagocytophiluminfection, Bindu Sukumaran; Yasunori Ogura; Joao H.F. Pedra; Koichi S. Kobayashi; Richard A. Flavell; Erol Fikrig, Nov. 2012, 66, 2, 211, 219, Scientific journal, 10.1111/j.1574-695x.2012.01001.x


  • Not Refereed, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, MDPI AG, BRCA1 and p53 Tumor Suppressor Molecules in Alzheimer's Disease, Atsuko Nakanishi; Akari Minami; Yasuko Kitagishi; Yasunori Ogura; Satoru Matsuda, Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer's disease. Alzheimer's disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer's disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer's disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer's disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field., Feb. 2015, 16, 2, 2879, 2892, Book review, 10.3390/ijms16022879
  • Not Refereed, JOURNAL OF BIOLOGICAL CHEMISTRY, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Host recognition of bacterial muramyl dipeptide mediated through NOD2, N Inohara; Y Ogura; A Fontalba; O Gutierrez; F Pons; J Crespo; K Fukase; S Inamura; S Kusumoto; M Hashimoto; SJ Foster; AP Moran; JL Fernandez-Luna; G Nunez, NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl. dipeptide (MurNAc-L-Ala-D-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement Of L-Ala for D-Ala or D-isoGIn for L-isoGIn eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOW but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOW mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOW mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development., Feb. 2003, 278, 8, 5509, 5512, 10.1074/jbc.C200673200
  • Not Refereed, GASTROENTEROLOGY, W B SAUNDERS CO, Systematic functional analysis of NOD2 reveals regulatory mechanisms and critical residues involved in muramyl dipeptide recognition, M Chamaillard; T Tanabe; Y Ogura; L Zhu; S Qiu; J Masumoto; P Ghosh; A Moran; MM Predergast; G Tromp; CJ Williams; N Inohara; G Nunez, Apr. 2004, 126, 4, A358, A359, Summary international conference


  • OGURA Yasunori, 日本家政学会関西支部第36回研究発表会, 香辛料抽出物による炎症性サイトカインIL-1βの分泌抑制について, Oct. 2016, False
  • OGURA Yasunori, 日本家政学会関西支部第36回研究発表会, ウシグソヒトヨタケの子実体形成について, Oct. 2014, 京都市, False
  • OGURA Yasunori, 日本家政学会第66回大会, 香辛料抽出液が炎症性サイトカインIL?1βの産生に与える影響, May 2014, 福岡県北九州市
  • OGURA Yasunori, 第10回日本栄養改善学会近畿支部学術総会, 栄養と免疫?特に自然免疫に関連して―, Dec. 2011, 日本栄養改善学会近畿支部, 奈良, False
  • OGURA Yasunori, 第152 回日本獣医学会学術集会日本比較薬理・毒性学会, インフラマソームによる炎症制御, Sep. 2011, 日本獣医学会, 大阪, False
  • OGURA Yasunori, 第83回日本細菌学会総会, Purification of multifunctional repeat-in-toxin (RTX) of Vibrio chlerae O1, Mar. 2010, 横浜, False
  • OGURA Yasunori, 第83回日本細菌学会総会, The TLRP3- and NLRC4-mediated inflammasome activation by the infection of Vibrio parahaemolyticus, Mar. 2010, 横浜, False
  • OGURA Yasunori, 第83回日本細菌学会総会, Caspase-1 activation by environmentally isolated bacteria, Mar. 2010, 横浜, False
  • OGURA Yasunori, 第83回日本細菌学会総会, Mechanism of macrophage infection by Leptospira interrogans, Mar. 2010, 横浜, False
  • OGURA Yasunori, 第39回日本免疫学会総会, Activation of the NLRP3 inflammasome by pathogenic Vibrios is mediated via pore-forming toxins and differentially regulated by Toll-like receptor signaling., Dec. 2009, 大阪, False
  • OGURA Yasunori, 第38回日本免疫学会総会, Vibrio vulnificus activates Nalp3 inflammasome via the synergistic action of pore forming toxins, Dec. 2008, 京都, False
  • OGURA Yasunori, 第78回日本生化学会大会, The NOD Protein Family: Role in Innate Immunity and Inflammatory Disease, Oct. 2005, 神戸, False
  • OGURA Yasunori; Chamaillard M; Tanabe T; Ogura Y; Zhu L; Qiu S; Masumoto J; Ghosh P; Moran A; Predergast MM; Tromp G; Williams CJ; Inohara N; Nunez G, The 105th Annual Meeting of the American Gastroenterolgical Association, Systematic functional analysis of NOD2 reveals regulatory mechanisms and critical residues involved in muramyl dipeptide recognition., May 2004, New Orleans, LA, USA, True
  • OGURA Yasunori, 第33回日本免疫学会総会, クローン病感受性遺伝子Nod2の小腸パネート細胞における発現, Dec. 2003, 福岡、2003年12月, False
  • OGURA Yasunori; Lala SG; Ogura Y; Hor SK; Abeya M; Osborne C; Davies S; Ogunbiyi O; Nunez G; Keshav S, The 2003 Annual Meeting of the British Society of Gastroenterology, Crohn's disease and the NOD2 gene: A role for Paneth cells., Mar. 2003, Birmingham, UK, True
  • OGURA Yasunori; Ogura Y, The 3rd International Meeting on Inflammatory Bowel Diseases in Capri, Genetic Variation and Activity of Mouse Nod2., 2003, Capri, Italy, True
  • OGURA Yasunori; Bonen DK; Ogura Y; Nicolae DL; Moran T; Karaliukas R; Ramos R; Turkyilmaz MA; Brant SR; Duerr RH; Cho JH; Nunez G, The 103rd Annual Meeting of the American Gastroenterolgical Association, Functional and genetic characterization of major CD-associated Nod2 variants., May 2002, San Francisco, CA, USA, True
  • OGURA Yasunori; Bonen DK; Ogura Y; Duerr RH; Brant SR; Nunez G; Cho JH, The American Society of Human genetics, 51st Annual Meeting, Ethnic specific differences in Nod2 associations to Crohn's disease. \nEthnic specific differences in Nod2 associations to Crohn's disease., Oct. 2001, San Diego, CA, USA, True
  • OGURA Yasunori, 第59回日本癌学会総会, アポトーシス・NF-κB活性化調節因子の構造と機能の共通性, Oct. 2000, 横浜, False
  • OGURA Yasunori, 第73回日本生化学会大会, アポトーシス・NF-κB活性化調節因子の構造と機能の共通性, Oct. 2000, 横浜, False
  • OGURA Yasunori, 第30回日本発生生物学会, Intraplacental yolk sacにおけるPDGF受容体α鎖の発現とその発生における役割, May 1997, 筑波, False


  • University of Michigan Inventor Recognition, University of Michigan, Yasunori Ogura, 2002
  • Crohn’s and Colitis Foundation of America, Research Fellowship Award, Crohn’s and Colitis Foundation of America, Yasunori Ogura, 2001

Industrial Property Rights

  • Patent right, NOD2 NUCLEIC ACIDS AND PROTEINS, OGURA Yasunori, Gabriel Nunez, Naohiro Inohara, Yasunori Ogura, Patent No. US 7,060,493B2

Copyright © MEDIA FUSION Co.,Ltd. All rights reserved.