Host Defense

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Innate immunity is a defense system triggered by pattern recognition receptors, which recognize various pathogens such as bacteria, fungi, and viruses, and induce the production of inflammatory factors to trigger immune responses. To gain comprehensive understanding of the molecular mechanisms responsible for innate immunity in vivo, our lab focuses on the following theme:

・Exploration of the relationship between immune responses and mechanisms that ensure mRNA stability

We have been investigating the comprehensive innate immune response induced by pattern recognition receptors that sense various pathogens. By studying the Toll-like receptor (TLR)-signaling pathway we found that a novel regulatory mechanism, “mRNA stability,” controls inflammatory responses. Regnase-1, an endoribonuclease, constitutively degrades mRNAs encoding inflammatory cytokines. Once the TLR pathway is activated, the synthesis of mRNAs encoding inflammatory cytokines is promptly induced along with reduced enzymatic activity of Regnase-1. As a result, mRNAs encoding inflammatory cytokines are stably expressed, resulting in an ongoing inflammatory response. Thus, endogenous Regnase-1 negatively regulates the stability of mRNAs encoding inflammatory cytokines in normal immune cells. Once pathogens invade cells, Regnase-1-mediated negative regulation is released, leading to inflammation.

figure1
The temporary inactivation of Reganse-1 upon cellular activation is also found in stimulation with other proinflammatory cytokines or T-cell activation, suggesting the importance of Reganse-1 protein modification for regulation of innate immune response. Furthermore, we have found that Regnase-1 not only regulates inflammation and immune activation but also plays a critical role in tissue homeostasis through the mRNA degradation. To understand the novel aspects of mRNA regulation by Regnase-1, we will identify the Reganse-1 target genes associated with RNA metabolism in immune and non-immune cells.

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Principal Investigator

Shizuo Akira Professor

Research field:Pathogen recognition and innate immunity
+81-6-6879-4940
sakirabiken.osaka-u.ac.jp
Education history
1977 Osaka University School of Medicine
1984 Osaka University, Graduate School of Medicine
Research and career history

1977-1980 Clinical Training and Physician
1985-1987 Research Fellow, University of California, Berkeley
1987-1995 Research Associate, Institute for Molecular and Cellular Biology, Osaka University
1995 Associate Professor, Institute for Molecular and Cellular Biology, Osaka University
1996-1999 Professor, Hyogo College of Medicine
1999-present Professor, Research Institute for Microbial Diseases, Osaka University
2007-2019.6 Director, Osaka University Immunology Frontier Research Center
2018 Specially Appointed Professor, Osaka University Immunology Frontier Research Center

Members

Kazuhiko Maeda Associate Professor
kazmaedabiken.osaka-u.ac.jp
Takashi Satoh Guest Professor
satoh.mbchtmd.ac.jp
Mikael Martino Associate Professor
mikael.martinomonash.edu
Kanako Kuniyoshi Assistant Professor
konkon0114ifrec.osaka-u.ac.jp
Hiroki Tanaka Assistant Professor
htanakaifrec.osaka-u.ac.jp
Shailendra Kumar Singh Researcher
singh-skifrec.osaka-u.ac.jp
Matias Jose Caldez Researcher
mjcaldezifrec.osaka-u.ac.jp
 
 

Publications

Kozaki T, Komano J, Kanbayashi D, Takahama M, Misawa T, Satoh T, Takeuchi O, Kawai T, Shimizu S, Matsuura Y, Akira S, Saitoh T. Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. Proc Natl Acad Sci U S A. 114(10): 2681-2686 (2017)
Satoh T, Nakagawa K, Sugihara F, Kuwahara R, Ashihara M, Yamane F, Minowa Y, Fukushima K, Ebina I, Yoshioka Y, Kumanogoh A, Akira S. Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature. 541(7635):96-101 (2017)
Satoh T, Akira S. Toll-Like Receptor Signaling and Its Inducible Proteins. Microbiol Spectr. 6, 4 (2016)
Maeda K, Akira S. TLR7 Structure: Cut in Z-Loop. Immunity. 45(4):705-707 (2016)
Martino MM, Maruyama K, Kuhn GA, Satoh T, Takeuchi O, Muller R, Akira S. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. Nature Communications. 7:11051 (2016)
Kuniyoshi K, Takeuchi O, Pandey S, Satoh T, Iwasaki H, Akira S, Kawai T. Pivotal role of RNA-binding E3 ubiquitin ligase mEX3C in RIG-I-mediated antiviral innate immunity. Proc Natl Acad Sci U S A. 111(15):5646-5651 (2014)
Lee H, Komano J, Saitoh Y, Yamaoka S, Kozaki T, Misawa T, Takahama M, Satoh T, Takeuchi O, Yamamoto N, Matsuura Y, Saitoh T, Akira S. Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus. Proc Natl Acad Sci U S A. 110(30):12379-12384 (2013)
Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K, Satoh T, Mino T, Suzuki Y, Standley DM, Tsujimura T, Rakugi H, Isaka Y, Takeuchi O, Akira S. Malt1-Induced Cleavage of Regnase-1 in CD4+ Helper T Cells Regulates Immune Activation. Cell. 153(5):1036-1049 (2013)
Zou J, Kawai T, Tsuchida T, Kozaki T, Tanaka H, Shin KS, Kumar H, Akira S. Poly IC Triggers a Cathepsin D- and IPS-1-Dependent Pathway to Enhance Cytokine Production and Mediate Dendritic Cell Necroptosis. Immunity. 38(49):717-728 (2013)
Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, Yoshioka Y, Morii E, Takakura N, Takeuchi O, Akira S. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature. 495(7442):524-528 (2013)
Misawa T, Takahama M, Kozaki T, LeeH, Zou J, Saitoh T, Akira S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 14(5):454-460 (2013)
Iwasaki H, Takeuchi O, Teraguchi S, Matsushita K, Uehata T, Kuniyoshi K, Satoh T, Saitoh T, Matsushita M, Standley DM, Akira S. The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol. 12(12):1167-1175 (2011)
Saitoh T, Satoh T, Yamamoto N, Uematsu S, Takeuchi O, Kawai T, Akira S. Antiviral Protein Viperin Promotes Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Type I Interferon Production in Plasmacytoid Dendritic Cells. Immunity. 34(3):352-63 (2011)
Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S. The Ubiquitin Ligase TRIM56 Regulates Innate Immune Responses to Intracellular Double-Stranded DNA. Immunity. 33(5):765-776 (2010)
Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 11(10):936-944 (2010)
Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci U S A. 107(4):1512-1517 (2010)
Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A. 106(49):20842-20846 (2009)
Kawagoe T, Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S. TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol. 10(9):965-972 (2009)
Matsushita K, Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H, Akira S. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature. 458(7242):1185-1190 (2009)
Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 456(7219):264-268 (2008)

Prize

2012 Frederik B. Bang Award(IEIIS)
2011 Gairdner International Award
2010 Keio Medical Science Prize
2010 Avery-Landsteiner Prize
2009 Person of Cultural Merit
2009 Foreign Associate, National Academy of Science
2007 Milstein Award
2007 The Japan Academy Award The Imperial Award
2007 Uehara Prize
2006 William B Coley Award
2006 Asahi Prize
2005 The Emperor's Purple Ribbon Medal
2004 Robert Koch Prize
2004 Prize of Pricess Takamatsu Cancer Reseach Fund
2003 Takeda Medical Prize
2002 Osaka Science Prize
2001 Hideyo Noguchi Prize
2000 Inoue Prize for Science

Editor/Editorial Board

Special mention

2016 Highly Cited Researchers “Biology & Biochemistry, Immunology” (Thomson Reuters)
2014 Highly Cited Researchers “Biology & Biochemistry”, “Clinical Medicine”, “Immunology” (Thomson Reuters)
2014 Lerner Lecture (Cleveland Clinic Lerner Research Institute, USA)
2014 Distinguished LUDWIG Lecture (Universite de Lausanne, Germany)
2010 17th Dundee Cell Signaling Lecture (University of Dundee, Scotland)
2009 Lacey Lecture (Washington University at St. Louis, Germany)
2008 Dyer Lecture (National Institutes of Health, USA)
2007 Dunham Lectures (Harvard Medical School, USA)
2007 Doctor of Medical Science at Technical University of Munich
2006 and 2007 "Hottest Researcher" in all research fields for two consecutive years (Thomson Scientific Research)
The top cited immunologist since 2004 (Thomson Scientific Research)