Immunology Frontier Research Center eC
Immunology Frontier Research Center eC
Tartey S.,Kyoto University |
Tartey S.,Japan Science and Technology Agency |
Tartey S.,Osaka University |
Matsushita K.,Hyogo College of Medicine |
And 14 more authors.
EMBO Journal | Year: 2014
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. Synopsis By recruiting SWI/SNF chromatin remodellers to NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. Akirin2 is critical for Toll-like receptor- and RIG-I-like receptor-induced cytokine production in mouse macrophages Akirin2 is critical for the responses to Listeria monocytogenes infection in living mice Akirin2 enables LPS-induced chromatin remodelling in a SWI/SNF-dependent manner The NF-κBp50-IκB-ζ-Akirin2 cascade is critical for the recruitment of Brg1, the SWI/SNF core catalytic subunit, to the Il6 promoter. By recruiting SWI/SNF chromatin remodellers to NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. © 2014 The Authors.
Kitai Y.,Nara Institute of Science and Technology |
Kitai Y.,Immunology Frontier Research Center eC |
Kitai Y.,Osaka University |
Takeuchi O.,Kyoto University |
And 7 more authors.
Journal of Biological Chemistry | Year: 2015
RIG-I-like receptors (RLRs), including retinoic acid-inducible gene-I (RIG-I) and MDA5, constitute a family of cytoplasmic RNA helicases that senses viral RNA and mounts antiviral innate immunity by producing type I interferons and inflammatory cytokines. Despite their essential roles in antiviral host defense,RLRsignaling is negatively regulated to protect the host from excessive inflammation and autoimmunity. Here, we identified ADP-ribosylation factor-like protein 5B (Arl5B), an Arl family small GTPase, as a regulator of RLR signaling through MDA5 but not RIG-I. Overexpression of Arl5B repressed interferon β promoter activation by MDA5 but not RIG-I, and its knockdown enhanced MDA5-mediated responses. Furthermore, Arl5B-deficient mouse embryonic fibroblast cells exhibited increased type I interferon expression in response toMDA5 agonists such as poly(I:C) and encephalomyocarditis virus. Arl5B-mediated negative regulation of MDA5 signaling does not require itsGTPbinding ability but requires Arl5B binding to the C-terminal domain of MDA5, which prevents interaction between MDA5 and poly(I:C). Our results, therefore, suggest that Arl5B is a negative regulator for MDA5. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
Uehata T.,Immunology Frontier Research Center eC |
Uehata T.,Osaka University |
Akira S.,Immunology Frontier Research Center eC |
Akira S.,Osaka University
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2013
Post-transcriptional regulation is a crucial step for coordinating immune responses. Post-transcriptional mechanisms exquisitely control inflammation by increasing or decreasing both the stability of mRNAs and the efficiency of protein translation. Regulatory RNase 1 (Regnase-1, also known as Zc3h12a or MCPIP1) was identified as a novel protein harboring a CCCH-type zinc-finger domain and a PIN-like RNase domain. Regnase-1 mRNA expression is induced by Toll-like receptor (TLR) ligands, interleukin (IL)-1β and MCP-1. Regnase-1 destabilizes mRNAs encoding immune related proteins including IL-6 and IL-12p40 via their 3' untranslated regions. In Regnase-1-deficient (-/-) macrophages, IL-6 is overproduced in response to LPS because Il6 mRNA is stabilized because of Regnase-1 deficiency. Regnase-1-/- mice developed severe systemic inflammation, characterized by production of autoantibodies. It is now known that Regnase-1 protein expression is dynamically regulated during the course of inflammation. Upon IL-1β and TLR stimulation, Regnase-1 is rapidly phosphorylated by IκB kinases (IKKs) and degraded via ubiquitin-proteasome machinery. Regnase-1 degradation allows Il6 mRNA to be expressed rapidly and robustly upon stimulation. Furthermore, Regnase-1 destabilizes its own mRNA, thereby preventing excessive translation of Regnase-1 and degradation of cytokine-encoding mRNAs. In this review, we will discuss the mechanism of Regnase-1-mediated mRNA decay and describe the mechanism by which Regnase-1 is tightly regulated in innate immune cells. This article is part of a Special Issue entitled: RNA Decay mechanisms. © 2013.