2022, Hokkaido University, Faculty of Medicine, Excellent Research Award　　　　　　　　　　　　　　　

2018, 武田科学振興財団, 武田報彰研究助成　　　　　　　　　　　　　　　

2009, Haartman Seminar, Haartman Institute, University of Helsinki　　　　　　　　　　　　　　　

Oct. 2006, Cancer Research Institute, Investigator Award　　　　　　　　　　　　　　　
Koichi S Kobayashi

2005, The Claudia Adams Barr Investigator　　　　　　　　　　　　　　　

2005, Fellow, Arthritis National Research Foundation　　　　　　　　　　　　　　　

Jul. 2004, Arthritis National Research Foundation, Fellow　　　　　　　　　　　　　　　
Koichi S Kobayashi

Jun. 1999, Cancer Research Institute, Postdoctoral Fellowship　　　　　　　　　　　　　　　
Koichi S Kobayashi

Mar. 1998, The Naito Foundation, The Naito Foundation Scholarship　　　　　　　　　　　　　　　
Koichi S Kobayashi

Epigenetic regulation of major histocompatibility complexes in gastrointestinal malignancies and the potential for clinical interception.
Jorge Enrique Tovar Perez, Shilan Zhang, William Hodgeman, Sabeeta Kapoor, Praveen Rajendran, Koichi S Kobayashi, Roderick H Dashwood
Clinical epigenetics, 16, 1, 83, 83, 24 Jun. 2024, [International Magazine]
English, Scientific journal, BACKGROUND: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. MAIN BODY: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. CONCLUSION: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

The balance between nuclear import and export of NLRC5 regulates MHC class I transactivation.
Baohui Zhu, Ryota Ouda, Ning An, Tsutomu Tanaka, Koichi S Kobayashi
The Journal of biological chemistry, 300, 5, 107205, 107205, May 2024, [International Magazine]
English, Scientific journal, Major histocompatibility complex (MHC) class I molecules play an essential role in regulating the adaptive immune system by presenting antigens to CD8 T cells. CITA (MHC class I transactivator), also known as NLRC5 (NLR family, CARD domain-containing 5), regulates the expression of MHC class I and essential components involved in the MHC class I antigen presentation pathway. While the critical role of the nuclear distribution of NLRC5 in its transactivation activity has been known, the regulatory mechanism to determine the nuclear localization of NLRC5 remains poorly understood. In this study, a comprehensive analysis of all domains in NLRC5 revealed that the regulatory mechanisms for nuclear import and export of NLRC5 coexist and counterbalance each other. Moreover, GCN5 (general control non-repressed 5 protein), a member of HATs (histone acetyltransferases), was found to be a key player to retain NLRC5 in the nucleus, thereby contributing to the expression of MHC class I. Therefore, the balance between import and export of NLRC5 has emerged as an additional regulatory mechanism for MHC class I transactivation, which would be a potential therapeutic target for the treatment of cancer and virus-infected diseases.

Brucella-driven host N-glycome remodeling controls infection.
Ana-Lucia Cabello, Kelsey Wells, Wenjing Peng, Hui-Qiang Feng, Junyao Wang, Damien F Meyer, Christophe Noroy, En-Shuang Zhao, Hao Zhang, Xueqing Li, Haowu Chang, Gabriel Gomez, Yuxin Mao, Kristin L Patrick, Robert O Watson, William K Russell, Aiying Yu, Jieqiang Zhong, Fengguang Guo, Mingqian Li, Mingyuan Zhou, Xiaoning Qian, Koichi S Kobayashi, Jianxun Song, Suresh Panthee, Yehia Mechref, Thomas A Ficht, Qing-Ming Qin, Paul de Figueiredo
Cell host & microbe, 32, 4, 588, 605, 10 Apr. 2024, [International Magazine]
English, Scientific journal, Many powerful methods have been employed to elucidate the global transcriptomic, proteomic, or metabolic responses to pathogen-infected host cells. However, the host glycome responses to bacterial infection remain largely unexplored, and hence, our understanding of the molecular mechanisms by which bacterial pathogens manipulate the host glycome to favor infection remains incomplete. Here, we address this gap by performing a systematic analysis of the host glycome during infection by the bacterial pathogen Brucella spp. that cause brucellosis. We discover, surprisingly, that a Brucella effector protein (EP) Rhg1 induces global reprogramming of the host cell N-glycome by interacting with components of the oligosaccharide transferase complex that controls N-linked protein glycosylation, and Rhg1 regulates Brucella replication and tissue colonization in a mouse model of brucellosis, demonstrating that Brucella exploits the EP Rhg1 to reprogram the host N-glycome and promote bacterial intracellular parasitism, thereby providing a paradigm for bacterial control of host cell infection.

NLRC5/MHC class I transactivator: A key target for immune escape by SARS-CoV-2.
Baohui Zhu, Ryota Ouda, Yusuke Kasuga, Paul de Figueiredo, Koichi S Kobayashi
BioEssays : news and reviews in molecular, cellular and developmental biology, 46, 4, e2300109, Apr. 2024, [International Magazine]
English, Scientific journal, Antigen presentation to CD8+ T cells by MHC class I molecules is essential for host defense against viral infections. Various mechanisms have evolved in multiple viruses to escape immune surveillance and defense to support viral proliferation in host cells. Through in vitro SARS-CoV-2 infection studies and analysis of COVID-19 patient samples, we found that SARS-CoV-2 suppresses the induction of the MHC class I pathway by inhibiting the expression and function of NLRC5, a major transcriptional regulator of MHC class I genes. In this review, we discuss the molecular mechanisms for suppression of the MHC class I pathway and clinical implications for COVID-19.

Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I.
Xin Sun, Toshiyuki Watanabe, Yoshitaka Oda, Weidong Shen, Alaa Ahmad, Ryota Ouda, Paul de Figueiredo, Hidemitsu Kitamura, Shinya Tanaka, Koichi S Kobayashi
Proceedings of the National Academy of Sciences of the United States of America, 121, 6, e2310821121, 06 Feb. 2024, [International Magazine]
English, Scientific journal, Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer.

FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA.
Yusuke Kasuga, Ryota Ouda, Masashi Watanabe, Xin Sun, Miki Kimura, Shigetsugu Hatakeyama, Koichi S Kobayashi
Proceedings of the National Academy of Sciences of the United States of America, 120, 24, e2218955120, 13 Jun. 2023, [International Magazine]
English, Scientific journal, Major histocompatibility complex (MHC) class I and II molecules play critical roles in the activation and regulation of adaptive immunity through antigen presentation to CD8+ and CD4+ T cells, respectively. Strict regulation of MHC expression is critical for proper immune responses. CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, is a master regulator of MHC class II (MHC-II) gene transcription. Although it has been known that CIITA activity is regulated at the transcriptional and protein levels, the mechanism to determine CIITA protein level has not been elucidated. Here, we show that FBXO11 is a bona fide E3 ligase of CIITA and regulates CIITA protein level through ubiquitination-mediated degradation. A nonbiased proteomic approach for CIITA-binding protein identified FBXO11, a member of the Skp1-Cullin-1-F-box E3 ligase complex, as a binding partner of CIITA but not MHC class I transactivator, NLRC5. The cycloheximide chase assay showed that the half-life of CIITA is mainly regulated by FBXO11 via the ubiquitin-proteasome system. The expression of FBXO11 led to the reduced MHC-II at the promoter activity level, transcriptional level, and surface expression level through downregulation of CIITA. Moreover, human and mouse FBXO11-deficient cells display increased levels of MHC-II and related genes. In normal and cancer tissues, FBXO11 expression level is negatively correlated with MHC-II. Interestingly, the expression of FBXO11, along with CIITA, is associated with prognosis of cancer patients. Therefore, FBXO11 is a critical regulator to determine the level of MHC-II, and its expression may serve as a biomarker for cancer.

Engineering live attenuated vaccines: Old dogs learning new tricks.
Julia Plocica, Fengguang Guo, Jugal Kishore Das, Koichi S Kobayashi, Thomas A Ficht, Robert C Alaniz, Jianxun Song, Paul de Figueiredo
Journal of translational autoimmunity, 6, 100198, 100198, 2023, [International Magazine]
English, Scientific journal, Autoimmune diseases such as rheumatoid arthritis and type 1 diabetes are increasingly common global problems. Concerns about increases in the prevalence of such diseases and the limited efficacy of conventional treatment regimens necessitates new therapies to address these challenges. Autoimmune disease severity and dysbiosis are interconnected. Although probiotics have been established as a therapy to rebalance the microbiome and suppress autoimmune symptoms, these microbes tend to lack a number of advantageous qualities found in non-commensal bacteria. Through attenuation and genetic manipulation, these non-commensal bacteria have been engineered into recombinant forms that offer malleable platforms capable of addressing the immune imbalances found in RA and T1D. Such bacteria have been engineered to express valuable gene products known to suppress autoimmunity such as anti-inflammatory cytokines, autoantigens, and enzymes synthesizing microbial metabolites. This review will highlight current and emerging trends in the field and discuss how they may be used to prevent and control autoimmune diseases.

ORF6, a repressor of the MHC class I pathway: new molecular target for SARS-CoV-2 drug discovery?
Baohui Zhu, Ryota Ouda, Paul de Figueiredo, Koichi S Kobayashi
Expert opinion on therapeutic targets, 27, 8, 639, 644, 2023, [International Magazine]
English

Regulation of MHC Class I Expression in Lung Epithelial Cells during Inflammation.
Justine Mathé, Mohamed Benhammadi, Koichi S Kobayashi, Sylvie Brochu, Claude Perreault
Journal of immunology (Baltimore, Md. : 1950), 208, 5, 1021, 1033, 01 Mar. 2022, [International Magazine]
English, Scientific journal, Lung infections are a perennial leading cause of death worldwide. The lung epithelium comprises three main cell types: alveolar type I (AT1), alveolar type II (AT2), and bronchiolar cells. Constitutively, these three cell types express extremely low amounts of surface MHC class I (MHC I) molecules, that is, <1% of levels found on medullary thymic epithelial cells (ECs). We report that inhalation of the TLR4 ligand LPS upregulates cell surface MHC I by ∼25-fold on the three subtypes of mouse lung ECs. This upregulation is dependent on Nlrc5, Stat1, and Stat2 and caused by a concerted production of the three IFN families. It is nevertheless hampered, particularly in AT1 cells, by the limited expression of genes instrumental in the peptide loading of MHC I molecules. Genes involved in production and response to cytokines and chemokines were selectively induced in AT1 cells. However, discrete gene subsets were selectively downregulated in AT2 or bronchiolar cells following LPS inhalation. Genes downregulated in AT2 cells were linked to cell differentiation and cell proliferation, and those repressed in bronchiolar cells were primarily involved in cilium function. Our study shows a delicate balance between the expression of transcripts maintaining lung epithelium integrity and transcripts involved in Ag presentation in primary lung ECs.

Metabolomics of Acute vs. Chronic Spinach Intake in an Apc–Mutant Genetic Background: Linoleate and Butanoate Metabolites Targeting HDAC Activity and IFN–γ Signaling
Ying-Shiuan Chen, Jia Li, Sultan Neja, Sabeeta Kapoor, Jorge Tovar Perez, Chakrapani Tripathi, Rani Menon, Arul Jayaraman, Kyongbum Lee, Wan Dashwood, Shan Wang, Ke Zhang, Koichi Kobayashi, Praveen Rajendran, Roderick Dashwood
Cells, 11, 3, 573, 573, MDPI AG, 07 Feb. 2022
Scientific journal, There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long–term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wild–type animals corroborated key contributions to anticancer outcomes by spinach–derived linoleate bioactives and a butanoate metabolite linked to increased α–diversity of the gut microbiome. Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction in colon tumors from rats given long–term spinach treatment. Mechanistic studies in cell–based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon–γ (IFN–γ) signaling axis. Clinical translation of these findings to at–risk patients might provide valuable quality–of–life benefits by delaying surgical interventions and drug therapies with adverse side effects.

A metabolically engineered bacterium controls autoimmunity and inflammation by remodeling the pro-inflammatory microenvironment.
Jugal Kishore Das, Fengguang Guo, Carrie Hunt, Shelby Steinmeyer, Julia A Plocica, Koichi S Kobayashi, Yufang Ding, Arul Jayaraman, Thomas A Ficht, Robert C Alaniz, Paul de Figueiredo, Jianxun Song
Gut microbes, 14, 1, 2143222, 2143222, 2022, [International Magazine]
English, Scientific journal, Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ∆vjbR, Bm∆vjbR::tnaA) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T (Treg) cells. We demonstrated that treatment with Bm∆vjbR::tnaA polarized macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Treg cells, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity, and reducing inflammation by remodeling the IME and augmenting Treg cell function.

Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment.
Fengguang Guo, Jugal K Das, Koichi S Kobayashi, Qing-Ming Qin, Thomas A Ficht, Robert C Alaniz, Jianxun Song, Paul De Figueiredo
Journal for immunotherapy of cancer, 10, 1, Jan. 2022, [International Magazine]
English, Scientific journal, The tumor microenvironment (TME) is characterized by the activation of immune checkpoints, which limit the ability of immune cells to attack the growing cancer. To overcome immune suppression in the clinic, antigen-expressing viruses and bacteria have been developed to induce antitumor immunity. However, the safety and targeting specificity are the main concerns of using bacteria in clinical practice as antitumor agents. In our previous studies, we have developed an attenuated bacterial strain (Brucella melitensis 16M ∆vjbR, henceforth Bm∆vjbR) for clinical use, which is safe in all tested animal models and has been removed from the select agent list by the Centers for Disease Control and Prevention. In this study, we demonstrated that Bm∆vjbR homed to tumor tissue and improved the TME in a murine model of solid cancer. In addition, live Bm∆vjbR promoted proinflammatory M1 polarization of tumor macrophages and increased the number and activity of CD8+ T cells in the tumor. In a murine colon adenocarcinoma model, when combined with adoptive transfer of tumor-specific carcinoembryonic antigen chimeric antigen receptor CD8+ T cells, tumor cell growth and proliferation was almost completely abrogated, and host survival was 100%. Taken together, these findings demonstrate that the live attenuated bacterial treatment can defeat cancer resistance to chimeric antigen receptor T-cell therapy by remodeling the TME to promote macrophage and T cell-mediated antitumor immunity.

SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis.
Ji-Seung Yoo, Michihito Sasaki, Steven X Cho, Yusuke Kasuga, Baohui Zhu, Ryota Ouda, Yasuko Orba, Paul de Figueiredo, Hirofumi Sawa, Koichi S Kobayashi
Nature communications, 12, 1, 6602, 6602, 15 Nov. 2021, [International Magazine]
English, Scientific journal, The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.

MHC class I transactivator NLRC5 in host immunity, cancer and beyond.
Steven X Cho, Saptha Vijayan, Ji-Seung Yoo, Toshiyuki Watanabe, Ryota Ouda, Ning An, Koichi S Kobayashi
Immunology, 162, 3, 252, 261, Mar. 2021, [International Magazine]
English, Scientific journal, The presentation of antigenic peptides by major histocompatibility complex (MHC) class I and class II molecules is crucial for activation of the adaptive immune system. The nucleotide-binding domain and leucine-rich repeat receptor family members CIITA and NLRC5 function as the major transcriptional activators of MHC class II and class I gene expression, respectively. Since the identification of NLRC5 as the master regulator of MHC class I and class-I-related genes, there have been major advances in understanding the function of NLRC5 in infectious diseases and cancer. Here, we discuss the biological significance and mechanism of NLRC5-dependent MHC class I expression.

NLRC5/CITA expression correlates with efficient response to checkpoint blockade immunotherapy.
Sayuri Yoshihama, Steven X Cho, Jason Yeung, Xuedong Pan, Gregory Lizee, Kranti Konganti, Valen E Johnson, Koichi S Kobayashi
Scientific reports, 11, 1, 3258, 3258, 05 Feb. 2021, [International Magazine]
English, Scientific journal, Checkpoint blockade-mediated immunotherapy is emerging as an effective treatment modality for multiple cancer types. However, cancer cells frequently evade the immune system, compromising the effectiveness of immunotherapy. It is crucial to develop screening methods to identify the patients who would most benefit from these therapies because of the risk of the side effects and the high cost of treatment. Here we show that expression of the MHC class I transactivator (CITA), NLRC5, is important for efficient responses to anti-CTLA-4 and anti-PD1 checkpoint blockade therapies. Melanoma tumors derived from patients responding to immunotherapy exhibited significantly higher expression of NLRC5 and MHC class I-related genes compared to non-responding patients. In addition, multivariate analysis that included the number of tumor-associated non-synonymous mutations, predicted neo-antigen load and PD-L2 expression was capable of further stratifying responders and non-responders to anti-CTLA4 therapy. Moreover, expression or methylation of NLRC5 together with total somatic mutation number were significantly correlated with increased patient survival. These results suggest that NLRC5 tumor expression, alone or together with tumor mutation load constitutes a valuable predictive biomarker for both prognosis and response to anti-CTLA-4 and potentially anti-PD1 blockade immunotherapy in melanoma patients.

IFN-λ Enhances Constitutive Expression of MHC Class I Molecules on Thymic Epithelial Cells.
Mohamed Benhammadi, Justine Mathé, Maude Dumont-Lagacé, Koichi S Kobayashi, Louis Gaboury, Sylvie Brochu, Claude Perreault
Journal of immunology (Baltimore, Md. : 1950), 205, 5, 1268, 1280, 01 Sep. 2020, [International Magazine]
English, Scientific journal, Regulation of MHC class I (MHC I) expression has been studied almost exclusively in hematolymphoid cells. We report that thymic epithelial cells (TECs), particularly the medullary TECs, constitutively express up to 100-fold more cell surface MHC I proteins than epithelial cells (ECs) from the skin, colon, and lung. Differential abundance of cell surface MHC I in primary ECs is regulated via transcription of MHC I and of genes implicated in the generation of MHC I-binding peptides. Superior MHC I expression in TECs is unaffected by deletion of Ifnar1 or Ifngr1, but is lessened by deletion of Aire, Ifnlr1, Stat1, or Nlrc5, and is driven mainly by type III IFN produced by medullary TECs. Ifnlr1 -/- mice show impaired negative selection of CD8 thymocytes and, at 9 mo of age, present autoimmune manifestations. Our study shows unanticipated variation in MHC I expression by ECs from various sites and provides compelling evidence that superior expression of MHC I in TECs is crucial for proper thymocyte education.

Green Tea Polyphenols Modify the Gut Microbiome in db/db Mice as Co-Abundance Groups Correlating with the Blood Glucose Lowering Effect.
Tingting Chen, Anna B Liu, Shili Sun, Nadim J Ajami, Matthew C Ross, Hong Wang, Le Zhang, Kenneth Reuhl, Koichi Kobayashi, Janet C Onishi, Liping Zhao, Chung S Yang
Molecular nutrition & food research, 63, 8, e1801064, Apr. 2019, [International Magazine]
English, Scientific journal, SCOPE: The effects of green tea polyphenols, Polyphenon E (PPE), and black tea polyphenols, theaflavins (TFs), on gut microbiota and development of diabetes in db/db mice are investigated and compared. METHODS AND RESULTS: Supplementation of PPE (0.1%) in the diet of female db/db mice for 7 weeks decreases fasting blood glucose levels and mesenteric fat while increasing the serum level of insulin, possibly through protection against β-cell damage. However, TFs are less or not effective. Microbiome analysis through 16S rRNA gene sequencing shows that PPE and TFs treatments significantly alter the bacterial community structure in the cecum and colon, but not in the ileum. The key bacterial phylotypes responding to the treatments are then clustered into 11 co-abundance groups (CAGs). CAGs 6 and 7, significantly increased by PPE but not by TFs, are negatively associated with blood glucose levels. The operational taxonomic units in these CAGs are from two different phyla, Firmicutes and Bacteroidetes. CAG 10, decreased by PPE and TFs, is positively associated with blood glucose levels. CONCLUSION: Gut microbiota respond to tea polyphenol treatments as CAGs instead of taxa. Some of the CAGs associated with the blood glucose lowering effect are enriched by PPE, but not TFs.

Class I transactivator, NLRC5: a central player in the MHC class I pathway and cancer immune surveillance.
Vijayan S, Sidiq T, Yousuf S, van den Elsen PJ, Kobayashi KS
Immunogenetics, 71, 3, 273, 282, Mar. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Major histocompatibility complex (MHC) class I and class II molecules play critical roles in the activation of the adaptive immune system by presenting antigens to CD8+ and CD4+ T cells, respectively. Although it has been well known that CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, as a master regulator of MHC class II gene expression, the mechanism of MHC class I gene transactivation was unclear. Recently, another NLR protein, NLRC5 (NLR family, CARD domain-containing 5), was identified as an MHC class I transactivator (CITA). NLRC5 is a critical regulator for the transcriptional activation of MHC class I genes and other genes involved in the MHC class I antigen presentation pathway. CITA/NLRC5 plays a crucial role in human cancer immunity through the recruitment and activation of tumor killing CD8+ T cells. Here, we discuss the molecular function and mechanism of CITA/NLRC5 in the MHC class I pathway and its role in cancer.

The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation.
Nechama M, Kwon J, Wei S, Kyi AT, Welner RS, Ben-Dov IZ, Arredouani MS, Asara JM, Chen CH, Tsai CY, Nelson KF, Kobayashi KS, Israel E, Zhou XZ, Nicholson LK, Lu KP
Nat Commun., 23;9(1):1603., 1, 1603, 1603, Apr. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation.

Quiescent Tissue Stem Cells Evade Immune Surveillance
Judith Agudo, Eun Sook Park, Samuel A. Rose, Eziwoma Alibo, Robert Sweeney, Maxime Dhainaut, Koichi S. Kobayashi, Ravi Sachidanandam, Alessia Baccarini, Miriam Merad, Brian D. Brown
Immunity, 48, 2, 271, 285.e5, Cell Press, 20 Feb. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP (vol 8, 15865, 2017)
Pradeep Bist, Wan Shoo Cheong, Aylwin Ng, Neha Dikshit, Bae Hoon Kim, Niyas Kudukkil Pulloor, Hanif Javanmard Khameneh, Matija Hedl, Avinash R. Shenoy, Vanniarajan Balamuralidhar, Najib Bin Abdul Malik, Michelle Hong, Albert Neutzner, Keh-Chuang Chin, Koichi S. Kobayashi, Antonio Bertoletti, Alessandra Mortellaro, Clara Abraham, John D. MacMicking, Ramnik J. Xavier, Bindu Sukumaran
NATURE COMMUNICATIONS, 8, 16141, 16141, Aug. 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP
Pradeep Bist, Wan Shoo Cheong, Aylwin Ng, Neha Dikshit, Bae-Hoon Kim, Niyas Kudukkil Pulloor, Hanif Javanmard Khameneh, Matija Hedl, Avinash R. Shenoy, Vanniarajan Balamuralidhar, Najib Bin Abdul Malik, Michelle Hong, Albert Neutzner, Keh-Chuang Chin, Koichi S. Kobayashi, Antonio Bertoletti, Alessandra Mortellaro, Clara Abraham, John D. MacMicking, Ramnik J. Xavier, Bindu Sukumaran
NATURE COMMUNICATIONS, 8, 15865, 15865, Jun. 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection
Aseem Pandey, Sheng Li Ding, Qing-Ming Qin, Rahul Gupta, Gabriel Gomez, Furong Lin, Xuehuan Feng, Luciana Fachini da Costa, Sankar P. Chaki, Madhu Katepalli, Elizabeth D. Case, Erin J. van Schaik, Tabasum Sidiq, Omar Khalaf, Angela Arenas, Koichi S. Kobayashi, James E. Samuel, Gonzalo M. Rivera, Robert C. Alaniz, Sing-Hoi Sze, Xiaoning Qian, William J. Brown, Allison Rice-Ficht, William K. Russell, Thomas A. Ficht, Paul de Figueiredo
CELL HOST & MICROBE, 21, 5, 637, +, May 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

NLRC5/CITA: A Key Player in Cancer Immune Surveillance
Sayuri Yoshihama, Saptha Vijayan, Tabasum Sidiq, Koichi S. Kobayashi
Trends in Cancer, 3, 1, 28, 38, Cell Press, 01 Jan. 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

Nod2: A Critical Regulator of Ileal Microbiota and Crohn's Disease
Tabasum Sidiq, Sayuri Yoshihama, Isaac Downs, Koichi S. Kobayashi
FRONTIERS IN IMMUNOLOGY, 7, 367, 367, Sep. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression
Isaac Downs, Saptha Vijayan, Tabasum Sidiq, Koichi S. Kobayashi
BIOFACTORS, 42, 4, 349, 357, Jul. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

NLRC5/MHC class I transactivator is a target for immune evasion in cancer
Sayuri Yoshihama, Jason Roszik, Isaac Downs, Torsten B. Meissner, Saptha Vijayan, Bjoern Chapuy, Tabasum Sidiq, Margaret A. Shipp, Gregory A. Lizee, Koichi S. Kobayashi
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113, 21, 5999, 6004, May 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal

Gastric LTi cells promote lymphoid follicle formation but are limited by IRAK-M and do not alter microbial growth
J. Shiu, M. B. Piazuelo, H. Ding, S. J. Czinn, M. L. Drakes, A. Banerjee, N. Basappa, K. S. Kobayashi, W. F. Fricke, T. G. Blanchard
MUCOSAL IMMUNOLOGY, 8, 5, 1047, 1059, Sep. 2015, [Peer-reviewed]
English, Scientific journal

Microbiota regulates type 1 diabetes through Toll-like receptors
Michael P. Burrows, Pavel Volchkov, Koichi S. Kobayashi, Alexander V. Chervonsky
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112, 32, 9973, 9977, Aug. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

Ubiquitination-mediated regulation of RIP2 in NOD2 signaling and MDP tolerance induction
Bindu Sukumaran, Pradeep Bist, Aywin Ng, Bae Hoon Kim, Niyas Kudukkil Pulloor, Hanif Khameneh, Matija Hedi, Neha Dikshit, Avinash Shenoy, Vanniarajan Balamuralidhar, Michelle Hong, Albert Neutzner, Keh-Chuang Chin, Koichi Kobayashi, Antonio Bertoletti, Alessandra Mortellaro, Clara Abraham, John MacMicking, Ramnik Xavier
JOURNAL OF IMMUNOLOGY, 194, May 2015
English

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection (Retraction of vol 80, pg 2558, 2012)
Balamayooran Theivanthiran, Sanjay Batra, Gayathriy Balamayooran, Shanshan Cai, Koichi Kobayashi, Richard A. Flavell, Samithamby Jeyaseelan
INFECTION AND IMMUNITY, 83, 5, 2199, 2199, May 2015
English

Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M
Masanori Miyata, Ji-Yun Lee, Seiko Susuki-Miyata, Wenzhuo Y. Wang, Haidong Xu, Hirofumi Kai, Koichi S. Kobayashi, Richard A. Flavell, Jian-Dong Li
NATURE COMMUNICATIONS, 6, 6062, 6062, Jan. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

Macrophage Phenotype Controls Long-Term AKI Outcomes-Kidney Regeneration versus Atrophy
Maciej Lech, Regina Groebmayr, Mi Ryu, Georg Lorenz, Ingo Hartter, Shrikant R. Mulay, Heni Eka Susanti, Koichi S. Kobayashi, Richard A. Flavell, Hans-Joachim Anders
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 25, 2, 292, 304, Feb. 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection (vol 80, pg 2558, 2012)
Balamayooran Theivanthiran, Sanjay Batra, Gayathriy Balamayooran, Shanshan Cai, Koichi Kobayashi, Richard A. Flavell, Samithamby Jeyaseelan
INFECTION AND IMMUNITY, 81, 11, 4324, 4324, Nov. 2013
English

IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to Helicobacter pylori
Jessica Shiu, Steven J. Czinn, Koichi S. Kobayashi, Yezhou Sun, Thomas G. Blanchard
PLOS ONE, 8, 6, e66914, Jun. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal

IRAK-M Deficiency Leads to Increased Gastric Lymphoid Aggregate Formation and Antibody Responses During H. pylori Infection
Jessica Shiu, Hua Ding, Koichi S. Kobayashi, Steven J. Czinn, Tom G. Blanchard
GASTROENTEROLOGY, 144, 5, S313, S313, May 2013
English

IRAK-M IN RENAL FIBROSIS UPON UNILATERAL URETERAL OBSTRUCTION
Maciej Lech, Roman Guenthner, Georg Lorenz, Mi Ryu, Regina Groebmayr, Heni Susanti, Koichi S. Kobayashi, Richard A. Flavell, Hans-Joachim Anders
NEPHROLOGY DIALYSIS TRANSPLANTATION, 28, 190, 190, May 2013
English

Altered Gut Microbiota Promotes Colitis-Associated Cancer in IL-1 Receptor-Associated Kinase M-Deficient Mice
Klara Klimesova, Miloslav Kverka, Zuzana Zakostelska, Tomas Hudcovic, Tomas Hrncir, Renata Stepankova, Pavel Rossmann, Jakub Ridl, Martin Kostovcik, Jakub Mrazek, Jan Kopecny, Koichi S. Kobayashi, Helena Tlaskalova-Hogenova
INFLAMMATORY BOWEL DISEASES, 19, 6, 1266, 1277, May 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal

Regulation of intestinal microbiota by the NLR protein family
Amlan Biswas, Koichi S. Kobayashi
INTERNATIONAL IMMUNOLOGY, 25, 4, 207, 214, Apr. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal

Shaping Intestinal Bacterial Community by TLR and NLR Signaling
Koichi S. Kobayashi
PROBIOTIC BACTERIA AND THEIR EFFECT ON HUMAN HEALTH AND WELL-BEING, 107, 32, 42, 2013, [Peer-reviewed]
English, Scientific journal

NLRC5: a key regulator of MHC class I-dependent immune responses
Koichi S. Kobayashi, Peter J. van den Elsen
NATURE REVIEWS IMMUNOLOGY, 12, 12, 813, 820, Dec. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal

Receptor interacting protein-2 contributes to host defense against Anaplasma phagocytophilum infection
Bindu Sukumaran, Yasunori Ogura, Joao H. F. Pedra, Koichi S. Kobayashi, Richard A. Flavell, Erol Fikrig
FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY, 66, 2, 211, 219, Nov. 2012, [Peer-reviewed]
English, Scientific journal

Proteasomal Degradation of Nod2 Protein Mediates Tolerance to Bacterial Cell Wall Components
Kyoung-Hee Lee, Amlan Biswas, Yuen-Joyce Liu, Koichi S. Kobayashi
JOURNAL OF BIOLOGICAL CHEMISTRY, 287, 47, 39800, 39811, Nov. 2012, [Peer-reviewed]
English, Scientific journal

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection (Retracted article. See vol. 83, pg. 2199, 2015)
Balamayooran Theivanthiran, Sanjay Batra, Gayathriy Balamayooran, Shanshan Cai, Koichi Kobayashi, Richard A. Flavell, Samithamby Jeyaseelan
INFECTION AND IMMUNITY, 80, 7, 2558, 2569, Jul. 2012, [Peer-reviewed]
English, Scientific journal

Cutting Edge: Impaired MHC Class I Expression in Mice Deficient for Nlrc5/Class I Transactivator
Amlan Biswas, Torsten B. Meissner, Taro Kawai, Koichi S. Kobayashi
JOURNAL OF IMMUNOLOGY, 189, 2, 516, 520, Jul. 2012, [Peer-reviewed]
English, Scientific journal

Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia
Jacobien J. Hoogerwerf, Gerritje J. W. van der Windt, Dana C. Blok, Arie J. Hoogendijk, Alex F. de Vos, Cornelis van 't Veer, Sandrine Florquin, Koichi S. Kobayashi, Richard A. Flavell, Tom van der Poll
MOLECULAR MEDICINE, 18, 7, 1067, 1075, Jul. 2012, [Peer-reviewed]
English, Scientific journal

NLRC5: a newly discovered MHC class I transactivator (CITA)
Torsten B. Meissner, Amy Li, Koichi S. Kobayashi
MICROBES AND INFECTION, 14, 6, 477, 484, Jun. 2012, [Peer-reviewed]
English

Interleukin 1 Receptor-Associated Kinase M Impairs Host Defense During Pneumococcal Pneumonia
Gerritje J. W. van der Windt, Dana C. Blok, Jacobien J. Hoogerwerf, Adriana J. J. Lammers, Alex F. de Vos, Cornelis van't Veer, Sandrine Florquin, Koichi S. Kobayashi, Richard A. Flavell, Tom van der Poll
JOURNAL OF INFECTIOUS DISEASES, 205, 12, 1849, 1857, Jun. 2012, [Peer-reviewed]
English, Scientific journal

Intracellular Invasion of Orientia tsutsugamushi Activates Inflammasome in ASC-Dependent Manner
Jung-Eun Koo, Hye-Jin Hong, Andrea Dearth, Koichi S. Kobayashi, Young-Sang Koh
PLOS ONE, 7, 6, e39042, Jun. 2012, [Peer-reviewed]
English, Scientific journal

NLRC5 Cooperates with the RFX Transcription Factor Complex To Induce MHC Class I Gene Expression
Torsten B. Meissner, Yuen-Joyce Liu, Kyoung-Hee Lee, Amy Li, Amlan Biswas, Marja C. J. A. van Eggermond, Peter J. van den Elsen, Koichi S. Kobayashi
JOURNAL OF IMMUNOLOGY, 188, 10, 4951, 4958, May 2012, [Peer-reviewed]
English, Scientific journal

Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1
Yun Zhao, Carmen Alonso, Isabel Ballester, Joo Hye Song, Sun Young Chang, Bayasi Guleng, Seiji Arihiro, Peter J. Murray, Ramnik Xavier, Koichi S. Kobayashi, Hans-Christian Reinecker
INFLAMMATORY BOWEL DISEASES, 18, 4, 603, 612, Apr. 2012, [Peer-reviewed]
English, Scientific journal

The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity
Torsten B. Meissner, Amy Li, Yuen-Joyce Liu, Etienne Gagnon, Koichi S. Kobayashi
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 418, 4, 786, 791, Feb. 2012, [Peer-reviewed]
English, Scientific journal

Molecular mechanism of downregualtion of MHC class I molecules in cancer
Koichi S. Kobayashi
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 30, S5, S5, 2012
English

TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2 (Proceedings of the National Academy of Sciences of the United States of America (2012) 109, 4 (E177-E186))
Delhase, M., Kim, S.-Y., Lee, H., Naiki-Ito, A., Chen, Y., Ahn, E.-R., Murata, K., Kim, S.-J., Lautsch, N., Kobayashi, K.S., Shirai, T., Karin, M., Nakanishi, M.
Proceedings of the National Academy of Sciences of the United States of America, 109, 11, 4332, 4335, 2012, [Peer-reviewed]
English, Scientific journal

Nod2: a key regulator linking microbiota to intestinal mucosal immunity
Amlan Biswas, Tanja Petnicki-Ocwieja, Koichi S. Kobayashi
JOURNAL OF MOLECULAR MEDICINE-JMM, 90, 1, 15, 24, Jan. 2012, [Peer-reviewed]
English

TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2.
Delhase M, Kim SY, Lee H, Naiki-Ito A, Chen Y, Ahn ER, Murata K, Kim SJ, Lautsch N, Kobayashi KS, Shirai T, Karin M, Nakanishi M
Proceedings of the National Academy of Sciences of the United States of America, 109, 4, E177, 86, Jan. 2012, [Peer-reviewed]
Scientific journal

NLRC5/CITA: a novel regulator of class I major histocompatibility complex genes.
Kobayashi KS
Journal of immunodeficiency & disorders, 1, 1, 2012, [Peer-reviewed]

Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus
Maciej Lech, Claudia Kantner, Onkar P. Kulkarni, Mi Ryu, Ekaterina Vlasova, Juergen Heesemann, David Anz, Stefan Endres, Koichi S. Kobayashi, Richard A. Flavell, Javier Martin, Hans-Joachim Anders
ANNALS OF THE RHEUMATIC DISEASES, 70, 12, 2207, 2217, Dec. 2011, [Peer-reviewed]
English, Scientific journal

Intrinsic expression of Nod2 in CD4(+) T lymphocytes is not necessary for the development of cell-mediated immunity and host resistance to Toxoplasma gondii
Braulia C. Caetano, Amlan Biswas, Djalma S. Lima-Junior, Luciana Benevides, Tiago W. P. Mineo, Catarina V. Horta, Kyoung-Hee Lee, Joao S. Silva, Ricardo T. Gazzinelli, Dario S. Zamboni, Koichi S. Kobayashi
EUROPEAN JOURNAL OF IMMUNOLOGY, 41, 12, 3627, 3631, Dec. 2011, [Peer-reviewed]
English, Scientific journal

Receptor-Interacting Protein 2 Controls Pulmonary Host Defense to Escherichia coli Infection via the Regulation of Interleukin-17A
Theivanthiran Balamayooran, Sanjay Batra, Gayathriy Balamayooran, Shanshan Cai, Koichi S. Kobayashi, Richard A. Flavell, Samithamby Jeyaseelan
INFECTION AND IMMUNITY, 79, 11, 4588, 4599, Nov. 2011, [Peer-reviewed]
English, Scientific journal

Muramyl dipeptide and its derivatives: peptide adjuvant in immunological disorders and cancer therapy.
Ogawa C, Liu YJ, Kobayashi KS
Current bioactive compounds, 7, 3, 180, 197, Sep. 2011, [Peer-reviewed]

Control of RIP2 Dependent Innate Immune Activation by GEF-111
Yun Zhao, Joo Hye Song, Carmen Alonso, Isabel Ballaster, Bayasi Guleng, Seiji Arihiro, Peter Murray, Ramnik J. Xavier, Koichi S. Kobayashi, Hans-Christian Reinecker
GASTROENTEROLOGY, 140, 5, S497, S497, May 2011
English

A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins
Kyoung-Hee Lee, Yuen-Joyce Liu, Amlan Biswas, Chikako Ogawa, Koichi S. Kobayashi
JOURNAL OF BIOLOGICAL CHEMISTRY, 286, 7, 5727, 5735, Feb. 2011, [Peer-reviewed]
English, Scientific journal

Nod2 Suppresses Borrelia burgdorferi Mediated Murine Lyme Arthritis and Carditis through the Induction of Tolerance
Tanja Petnicki-Ocwieja, Alicia S. DeFrancesco, Erin Chung, Courtney T. Darcy, Roderick T. Bronson, Koichi S. Kobayashi, Linden T. Hu
PLOS ONE, 6, 2, e17414, Feb. 2011, [Peer-reviewed]
English, Scientific journal

Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine
Amlan Biswas, Jeanette Wilmanski, Huamei Forsman, Tomas Hrncir, Liming Hao, Helena Tlaskalova-Hogenova, Koichi S. Kobayashi
EUROPEAN JOURNAL OF IMMUNOLOGY, 41, 1, 182, 194, Jan. 2011, [Peer-reviewed]
English, Scientific journal

The pattern recognition receptors Nod1 and Nod2 account for neutrophil recruitment to the lungs of mice infected with Legionella pneumophila
Mariana S. Frutuoso, Juliana I. Hori, Marcelo S. F. Pereira, Djalma S. L. Junior, Fabiane Sonego, Koichi S. Kobayashi, Richard A. Flavell, Fernando Q. Cunha, Dario S. Zamboni
MICROBES AND INFECTION, 12, 11, 819, 827, Oct. 2010, [Peer-reviewed]
English, Scientific journal

IL-1 Receptor-associated Kinase M Downregulates DSS-induced Colitis
Martin Berglund, Silvia Melgar, Koichi S. Kobayashi, Richard A. Flavell, Elisabeth Hultgren Hornquist, Olof H. Hultgren
INFLAMMATORY BOWEL DISEASES, 16, 10, 1778, 1786, Oct. 2010, [Peer-reviewed]
English, Scientific journal

NLR family member NLRC5 is a transcriptional regulator of MHC class I genes
Torsten B. Meissner, Amy Li, Amlan Biswas, Kyoung-Hee Lee, Yuen-Joyce Liu, Erkan Bayir, Dimitrios Iliopoulos, Peter J. van den Elsen, Koichi S. Kobayashi
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107, 31, 13794, 13799, Aug. 2010, [Peer-reviewed]
English, Scientific journal

Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum
Amlan Biswas, Yuen-Joyce Liu, Liming Hao, Atsushi Mizoguchi, Nita H. Salzman, Charles L. Bevins, Koichi S. Kobayashi
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107, 33, 14739, 14744, Aug. 2010, [Peer-reviewed]
English, Scientific journal

MyD88-Dependent Signaling Contributes to Host Defense against Ehrlichial Infection
Young-Sang Koh, Jung-Eun Koo, Amlan Biswas, Koichi S. Kobayashi
PLOS ONE, 5, 7, e11758, Jul. 2010, [Peer-reviewed]
English, Scientific journal

Cooperation between Multiple Microbial Pattern Recognition Systems Is Important for Host Protection against the Intracellular Pathogen Legionella pneumophila
Kristina A. Archer, Florence Ader, Koichi S. Kobayashi, Richard A. Flavell, Craig R. Roy
INFECTION AND IMMUNITY, 78, 6, 2477, 2487, Jun. 2010, [Peer-reviewed]
English, Scientific journal

Identification of Drosophila Yin and PEPT2 as Evolutionarily Conserved Phagosome-associated Muramyl Dipeptide Transporters
Guillaume M. Charriere, W. K. Eddie Ip, Stephanie Dejardin, Laurent Boyer, Anna Sokolovska, Michael P. Cappillino, Bobby J. Cherayil, Daniel K. Podolsky, Koichi S. Kobayashi, Neal Silverman, Adam Lacy-Hulbert, Lynda M. Stuart
JOURNAL OF BIOLOGICAL CHEMISTRY, 285, 26, 20147, 20154, Jun. 2010, [Peer-reviewed]
English, Scientific journal

A Role for IL-1 Receptor-Associated Kinase-M in Prostaglandin E-2-Induced Immunosuppression Post-Bone Marrow Transplantation
Leah L. N. Hubbard, Megan N. Ballinger, Peedikayil E. Thomas, Carol A. Wilke, Theodore J. Standiford, Koichi S. Kobayashi, Richard A. Flavell, Bethany B. Moore
JOURNAL OF IMMUNOLOGY, 184, 11, 6299, 6308, Jun. 2010, [Peer-reviewed]
English, Scientific journal

Cutting Edge: Nucleotide-Binding Oligomerization Domain 1-Dependent Responses Account for Murine Resistance against Trypanosoma cruzi Infection
Grace K. Silva, Fredy R. S. Gutierrez, Paulo M. M. Guedes, Catarina V. Horta, Larissa D. Cunha, Tiago W. P. Mineo, Juliana Santiago-Silva, Koichi S. Kobayashi, Richard A. Flavell, Joao S. Silva, Dario S. Zamboni
JOURNAL OF IMMUNOLOGY, 184, 3, 1148, 1152, Feb. 2010, [Peer-reviewed]
English, Scientific journal

Nod2 is required for the regulation of commensal microbiota in the intestine
Tanja Petnicki-Ocwieja, Tomas Hrncir, Yuen-Joyce Liu, Amlan Biswas, Tomas Hudcovic, Helena Tlaskalova-Hogenova, Koichi S. Kobayashi
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 106, 37, 15813, 15818, Sep. 2009, [Peer-reviewed]
English, Scientific journal

Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1
Pierre Sicard, Sebastien Jacquet, Koichi S. Kobayashi, Richard A. Flavell, Michael S. Marber
CARDIOVASCULAR RESEARCH, 83, 2, 277, 284, Jul. 2009, [Peer-reviewed]
English, Scientific journal

Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis
Didi Matza, Abdallah Badou, Mithilesh K. Jha, Tim Willinger, Andrey Antov, Shomyseh Sanjabi, Koichi S. Kobayashi, Vincent T. Marchesi, Richard A. Flavell
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 106, 24, 9785, 9790, Jun. 2009, [Peer-reviewed]
English, Scientific journal

Activation of nucleotide oligomerization domain 2 exacerbates a murine model of proteoglycan-induced arthritis
H. L. Rosenzweig, M. M. Jann, T. T. Glant, T. M. Martin, S. R. Planck, W. van Eden, P. J. S. van Kooten, R. A. Flavell, K. S. Kobayashi, J. T. Rosenbaum, M. P. Davey
JOURNAL OF LEUKOCYTE BIOLOGY, 85, 4, 711, 718, Apr. 2009, [Peer-reviewed]
English, Scientific journal

NOD2-Deficient Mice Have Impaired Resistance to Mycobacterium tuberculosis Infection through Defective Innate and Adaptive Immunity
Maziar Divangahi, Serge Mostowy, Francois Coulombe, Robert Kozak, Loic Guillot, Frederic Veyrier, Koichi S. Kobayashi, Richard A. Flavell, Philippe Gros, Marcel A. Behr
JOURNAL OF IMMUNOLOGY, 181, 10, 7157, 7165, Nov. 2008, [Peer-reviewed]
English, Scientific journal

Type IV Secretion-Dependent Activation of Host MAP Kinases Induces an Increased Proinflammatory Cytokine Response to Legionella pneumophila
Sunny Shin, Christopher L. Case, Kristina A. Archer, Catarina V. Nogueira, Koichi S. Kobayashi, Richard A. Flavell, Craig R. Roy, Dario S. Zamboni
PLOS PATHOGENS, 4, 11, e1000220, Nov. 2008, [Peer-reviewed]
English, Scientific journal

Role of the protein kinase TBK1 in TNF alpha-induced apoptosis
Mireille Delhase, Takashi Yagi, Koichi S. Kobayashi, Makoto Nakanishi
CYTOKINE, 43, 3, 326, 326, Sep. 2008
English

The role of RIP2 in p38 MAPK activation in the stressed heart
Sebastien Jacquet, Yasuhiro Nishino, Sarawut Kumphune, Pierre Sicard, James E. Clark, Koichi S. Kobayashi, Richard A. Flavell, Jan Eickhoff, Matt Cotten, Michael S. Marber
JOURNAL OF BIOLOGICAL CHEMISTRY, 283, 18, 11964, 11971, May 2008, [Peer-reviewed]
English, Scientific journal

NLR proteins: integral members of innate immunity and mediators of inflammatory diseases
Jeanette M. Wilmanski, Tanja Petnicki-Ocwieja, Koichi S. Kobayashi
JOURNAL OF LEUKOCYTE BIOLOGY, 83, 1, 13, 30, Jan. 2008, [Peer-reviewed]
English

A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation
Didi Matza, Abdallah Badou, Koichi S. Kobayashi, Karen Goldsmith-Pestana, Yutaka Masuda, Akihiko Komuro, Diane McMahon-Pratt, Vincent T. Marchesi, Richard A. Flavell
IMMUNITY, 28, 1, 64, 74, Jan. 2008, [Peer-reviewed]
English, Scientific journal

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
JOURNAL OF LEUKOCYTE BIOLOGY, 82, 1, 177, 183, Jul. 2007, [Peer-reviewed]
English, Scientific journal

Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells
ML Shinohara, LR Lu, J Bu, MBF Werneck, KS Kobayashi, LH Glimcher, H Cantor
NATURE IMMUNOLOGY, 7, 5, 498, 506, May 2006, [Peer-reviewed]
English, Scientific journal

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
NATURE IMMUNOLOGY, 7, 3, 318, 325, Mar. 2006, [Peer-reviewed]
English, Scientific journal

IL-1-receptor-associated kinase M is a central regulator of osteoclast differentiation and activation
HM Li, E Cuartas, WG Cui, YW Choi, TD Crawford, HZ Ke, KS Kobayashi, RA Flavell, A Vignery
JOURNAL OF EXPERIMENTAL MEDICINE, 201, 7, 1169, 1177, Apr. 2005, [Peer-reviewed]
English, Scientific journal

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
SCIENCE, 307, 5710, 731, 734, Feb. 2005, [Peer-reviewed]
English, Scientific journal

Shielding the double-edged sword: negative regulation of the innate immune system
KS Kobayashi, RA Flavell
JOURNAL OF LEUKOCYTE BIOLOGY, 75, 3, 428, 433, Mar. 2004, [Peer-reviewed]
English, Scientific journal

Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice
S Chakrabarti, KS Kobayashi, RA Flavell, CB Marks, K Miyake, DR Liston, KT Fowler, FS Gorelick, NW Andrews
JOURNAL OF CELL BIOLOGY, 162, 4, 543, 549, Aug. 2003, [Peer-reviewed]
English, Scientific journal

Intracellular debugging
KS Kobayashi, EE Eynon, RA Flavell
NATURE IMMUNOLOGY, 4, 7, 652, 654, Jul. 2003, [Peer-reviewed]
English

NLRC5のがんと免疫療法における役割　　　　　　　　　　　　　　　
應田涼太, 吉濱小百合, 春日優介, 坐間のゆり, 小林弘一, 77, 1, 114, 120, Jan. 2022, [Corresponding author]

細菌パターン認識受容体NOD2の腸管免疫における役割　　　　　　　　　　　　　　　
應田涼太, 尾野純也, 吉濱小百合, 小林弘一, 臨床免疫・アレルギー科, 70, 5, 497, 502, 2018

クローン病の病態理解に役立つNOD2の基礎　　　　　　　　　　　　　　　
吉濱小百合, 小林弘一, 11, 1, 13, 18, Nov. 2017, [Corresponding author]

NLRC5/CITA : the role in cancer immune evasion
吉濱小百合, 小林弘一, 臨床免疫・アレルギー科, 66, 6, 400, 406, Oct. 2016, [Corresponding author]
科学評論社, Japanese

体の中の”小さな生態系”腸内フローラによる免疫ホメオスタシスNOD2による消化管恒常性維持機構　　　　　　　　　　　　　　　
小林弘一
Nov. 2011, [Single work]

自然免疫TLRのネガティブフィードバック調節機構　　　　　　　　　　　　　　　
小林弘一, 佐藤あやの
Dec. 2003

エピゲノム編集を用いた新規肺癌免疫療法の開発
科学研究費助成事業
30 Jun. 2023 - 31 Mar. 2025
小林 弘一, 田中 努
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 23K18207

Development of novel anti-viral therapeuticing an advanced screening technologys us
Grants-in-Aid for Scientific Research
07 Oct. 2022 - 31 Mar. 2025
小林 弘一, 田村 友和, 福原 崇介, 應田 涼太
Japan Society for the Promotion of Science, Fund for the Promotion of Joint International Research (Fostering Joint International Research (B)), Hokkaido University, 22KK0112

The role of MHC class I transactivator NLRC5 in COVID-19
Grants-in-Aid for Scientific Research
01 Apr. 2022 - 31 Mar. 2025
小林 弘一, 澤 洋文, 福原 崇介, 應田 涼太
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 22H02883

プロテオーム解析とCROP-seq技術を用いた新規MHC-I遺伝子誘導因子の同定
科学研究費助成事業
30 Jul. 2020 - 31 Mar. 2022
小林 弘一, 畠山 鎮次, 應田 涼太
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 20K21511

Novel biomarkers for the immune checkpoint inhibitors for cancer
Grants-in-Aid for Scientific Research
24 Aug. 2018 - 31 Mar. 2020
Kobayashi Koichi
We recently found that NLRC5/MHC class I transactivator (CITA) is a mastery transcriptional coactivator of MHC class I genes as well as genes involved in the MHC-I dependent antigen presentation pathway. Moreover, we discovered that NLRC5-mediated MHC class I transactivation pathway constitutes a major mechanism for immune evasion in multiple cancers and NLRC5 expression was significantly associated with activation of CD8 cytotoxic T cells and patient survival in melanoma and other cancers. In this proposal, we analyzed the effectiveness of NLRC5 as a prognostic and predictive biomarker in melanoma. We have analyzed the melanoma patient cohort who received anti-CTLA4 therapy or anti-PD1 therapy. Our data showed that the expression level is associated with the response to checkpoint blocking therapies. This study suggests that NLRC5 expression would be an useful biomarker to determine the appropriate therapy for the cancer patients.
Japan Society for the Promotion of Science, Grant-in-Aid for Research Activity Start-up, Hokkaido University, 19K21250