2016 Fiscal Year Annual Research Report
ＭＡＰＫシグナルに関連したＡｒｉｄ５ａタンパク質分解機構の解明
| Project/Area Number |
15F15907
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| Research Institution | Osaka University |
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Principal Investigator |
岸本 忠三 大阪大学, 免疫学フロンティア研究センター, 特任教授 (10093402)
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| Co-Investigator(Kenkyū-buntansha) |
NYATI Kishan Kumar 大阪大学, 免疫学フロンティア研究センター, 外国人特別研究員
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| Project Period (FY) |
2015-10-09 – 2018-03-31
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| Keywords | Immune Regulation / IL-6 / Arid5a / Phosphorylation / Degradation / Ubiquitination |
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| Outline of Annual Research Achievements |
Recently, we identified a novel RNA binding protein (RBP), AT-rich interactive domain 5a (Arid5a), which stabilizes IL-6 but not TNF-α mRNA through binding to the 3’ untranslated region (UTR) of IL-6 mRNA. However, the signaling pathways underlying Arid5a-mediated regulation of IL-6 mRNA stability are largely uncharacterized. Here, we found that during the early phase of lipopolysaccharide (LPS) stimulation, NF-κB and an NF-κB-triggered IL-6-positive feedback loop activate Arid5a gene expression, increasing IL-6 expression via stabilization of the IL-6 mRNA. Subsequently, mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) promotes translocation of AU-rich element RNA-binding protein 1 (AUF-1) from the nucleus to the cytoplasm, where it destabilizes Arid5a mRNA by binding to AU-rich elements in the 3’ UTR. This results in down-regulation of IL-6 mRNA expression. During the late phase of LPS stimulation, p38 MAPK phosphorylates Arid5a and recruits the WW domain containing E3 ubiquitin protein ligase 1 (WWP1) to its complex, which in turn ubiquitinates Arid5a in a K48-linked manner, leading to its degradation. Inhibition of Arid5a phosphorylation and degradation increases production of IL-6 mRNA. Thus, our data demonstrate that LPS-induced NF-κB and MAPK signaling are required to control the regulation of the IL-6 mRNA stabilizing molecule Arid5a. This study therefore substantially increases our understanding of the mechanisms by which IL-6 is regulated.
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| Research Progress Status |
翌年度、交付申請を辞退するため、記入しない。
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| Strategy for Future Research Activity |
翌年度、交付申請を辞退するため、記入しない。
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[Journal Article] TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a.2017
Author(s)
Nyati KK, Masuda K, Zaman MM, Dubey PK, Millrine D, Chalise JP, Higa M, Li S, Standley DM, Saito K, Hanieh H, Kishimoto T.
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Journal Title
Nucleic Acids Res.
Volume: 45
Pages: 2687-2703
DOI
Peer Reviewed / Acknowledgement Compliant
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