Immunology Frontier Research Center eC
Immunology Frontier Research Center eC
Maruyama K.,Osaka University |
Maruyama K.,Immunology Frontier Research Center eC |
Takemura N.,Chiba University |
Takemura N.,Tokyo International University |
And 5 more authors.
Pharmacological Research | Year: 2017
The netrin family of proteins are involved in axon guidance during central nervous system development. In vertebrates, two membrane bound forms and five secreted forms of netrin have been reported. In addition to their critical role in neural morphogenesis, a growing number of reports suggest that netrin family proteins also play a role in inflammatory conditions, angiogenesis, and tumorigenesis. In these processes, Unc5 and DCC family proteins serve as receptors of netrin proteins. Recently, it was reported that some netrin family proteins may be involved in the pathogenesis of skeletal diseases including osteoporosis and arthritis. For example, administration of secreted netrin family proteins such as netrin 1 and netrin 4 has prophylactic potential in pathogenic bone degradation in mice. However, netrin 1 blocking antibody also protects mice from inflammatory bone destruction. Therefore, netrin family proteins are involved in the regulation of bone homeostasis, but their bona fide roles in the skeletal system remain controversial. In this review, we discuss the osteo-innate-immune functions of the netrin family of proteins, and summarize their therapeutic potential. © 2017 Elsevier Ltd
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.