title: Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex.
abstract: Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.
authors.affiliation: Laboratory of Infection and Prevention Institute for Virus Research Kyoto University, Sakyo-ku Kyoto, Japan CREST JST, Sakyo-ku Kyoto, Japan Laboratory of Host Defense WPI Immunology Frontier Research Center (IFReC), Osaka University Suita, Osaka, Japan Research Institute for Microbial Diseases Osaka University, Suita Osaka, Japan.
authors.forename: Sarang
authors.initials: S
authors.lastname: Tartey
authors.affiliation: Laboratory of Allergic Diseases Institute for Advanced Medical Sciences Hyogo College of Medicine, Suita Osaka, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Laboratory of Systems Immunology WPI Immunology Frontier Research Center (IFReC), Nishinomiya Hyogo, Japan.
authors.forename: Alexis
authors.initials: A
authors.lastname: Vandenbon
authors.affiliation: Laboratory of Infection and Prevention Institute for Virus Research Kyoto University, Sakyo-ku Kyoto, Japan CREST JST, Sakyo-ku Kyoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ori
authors.affiliation: Laboratory of Infection and Prevention Institute for Virus Research Kyoto University, Sakyo-ku Kyoto, Japan CREST JST, Sakyo-ku Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Laboratory of Infection and Prevention Institute for Virus Research Kyoto University, Sakyo-ku Kyoto, Japan CREST JST, Sakyo-ku Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mino
authors.affiliation: Laboratory of Systems Immunology WPI Immunology Frontier Research Center (IFReC), Nishinomiya Hyogo, Japan.
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.affiliation: IBMC UPR 9022 CNRS, Strasbourg Cedex, France.
authors.forename: Jules A
authors.initials: JA
authors.lastname: Hoffmann
authors.affiliation: IBMC UPR 9022 CNRS, Strasbourg Cedex, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Reichhart
authors.affiliation: Laboratory of Host Defense WPI Immunology Frontier Research Center (IFReC), Osaka University Suita, Osaka, Japan Research Institute for Microbial Diseases Osaka University, Suita Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Laboratory of Infection and Prevention Institute for Virus Research Kyoto University, Sakyo-ku Kyoto, Japan CREST JST, Sakyo-ku Kyoto, Japan Laboratory of Host Defense WPI Immunology Frontier Research Center (IFReC), Osaka University Suita, Osaka, Japan otake@virus.kyoto-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C559423:Akirin2 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D046912:Multiprotein Complexes; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins
keywords: chromatin remodeling; cytokine; gene regulation; innate immunity; macrophages
references.citation: Nat Rev Immunol. 2006 Sep;6(9):644-58
references.pmid: 16932750
references.citation: Exp Cell Res. 2008 Mar 10;314(5):1013-29
references.pmid: 18255059
references.citation: Mol Cell Biol. 2004 Mar;24(6):2385-96
references.pmid: 14993278
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11423-8
references.pmid: 20534538
references.citation: Genes Dev. 2006 Feb 1;20(3):282-96
references.pmid: 16452502
references.citation: EMBO J. 2012 Jan 18;31(2):301-16
references.pmid: 22068056
references.citation: Nature. 2009 Sep 10;461(7261):193-8
references.pmid: 19741699
references.citation: Cell. 2000 Nov 10;103(4):667-78
references.pmid: 11106736
references.citation: Nature. 2008 Jul 24;454(7203):428-35
references.pmid: 18650913
references.citation: Annu Rev Biochem. 2009;78:273-304
references.pmid: 19355820
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19438-43
references.pmid: 20974955
references.citation: Nature. 2004 Jul 8;430(6996):218-22
references.pmid: 15241416
references.citation: Nature. 2010 Apr 29;464(7293):1381-5
references.pmid: 20383124
references.citation: Genes Dev. 2005 Jul 15;19(14):1662-7
references.pmid: 15985610
references.citation: Nature. 2009 Jun 4;459(7247):708-11
references.pmid: 19396158
references.citation: Science. 2013 Feb 15;339(6121):786-91
references.pmid: 23258413
references.citation: Nat Immunol. 2008 Jan;9(1):97-104
references.pmid: 18066067
references.citation: J Biol Chem. 2005 Mar 4;280(9):7444-51
references.pmid: 15618216
references.citation: Nat Immunol. 2001 Jan;2(1):51-7
references.pmid: 11135578
references.citation: Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208
references.pmid: 15738986
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: Nature. 2009 Apr 30;458(7242):1185-90
references.pmid: 19322177
references.citation: BMC Evol Biol. 2009 Feb 06;9:34
references.pmid: 19200367
references.citation: Immunity. 2013 Mar 21;38(3):450-60
references.pmid: 23453632
references.citation: Nat Immunol. 2011 Jul 19;12(8):695-708
references.pmid: 21772278
references.citation: FEBS J. 2010 Mar;277(6):1453-64
references.pmid: 20148946
references.citation: J Mol Biol. 2005 Sep 16;352(2):329-37
references.pmid: 16083904
references.citation: Nat Immunol. 2010 Oct;11(10):936-44
references.pmid: 20729857
references.citation: Immunol Rev. 2009 Jan;227(1):248-63
references.pmid: 19120489
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17680-5
references.pmid: 20876105
references.citation: Nature. 2004 Nov 4;432(7013):107-12
references.pmid: 15525990
references.citation: Nat Rev Immunol. 2009 Oct;9(10):692-703
references.pmid: 19859064
references.citation: Methods Enzymol. 2004;377:299-316
references.pmid: 14979033
references.citation: Immunity. 1999 Dec;11(6):665-75
references.pmid: 10626889
references.citation: Exp Cell Res. 2009 Jul 15;315(12):2012-21
references.pmid: 19406121
references.citation: J Biol Chem. 2001 Jul 20;276(29):27657-62
references.pmid: 11356851
references.citation: J Biol Chem. 2008 May 2;283(18):12468-77
references.pmid: 18319258
references.citation: Nat Immunol. 2012 May 20;13(7):659-66
references.pmid: 22610141
references.citation: J Biol Chem. 2004 Apr 16;279(16):16677-86
references.pmid: 14701856
references.citation: Cell. 1995 Jan 27;80(2):321-30
references.pmid: 7834752
references.citation: Genes Dev. 2012 Dec 15;26(24):2673-83
references.pmid: 23222103
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D64-9
references.pmid: 23155063
references.citation: Cell. 2012 Jul 20;150(2):279-90
references.pmid: 22817891
references.citation: Science. 2003 Dec 5;302(5651):1727-36
references.pmid: 14605208
references.citation: Mol Cell Biol. 2003 Sep;23(17):6210-20
references.pmid: 12917342
references.citation: Genes Dev. 1999 Sep 15;13(18):2369-74
references.pmid: 10500094
references.citation: PLoS Genet. 2012;8(3):e1002547
references.pmid: 22396663
references.citation: Mol Cell. 2013 Jan 24;49(2):283-97
references.pmid: 23219531