PMID- 28168301 OWN - NLM STAT- MEDLINE DCOM- 20170808 LR - 20191210 IS - 1362-4962 (Electronic) IS - 0305-1048 (Print) IS - 0305-1048 (Linking) VI - 45 IP - 5 DP - 2017 Mar 17 TI - TLR4-induced NF-kappaB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a. PG - 2687-2703 LID - 10.1093/nar/gkx064 [doi] AB - The AT-rich interactive domain-containing protein 5a (Arid5a) plays a critical role in autoimmunity by regulating the half-life of Interleukin-6 (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-kappaB and an NF-kappaB-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 downregulation 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-kappaB 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. CI - (c) The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. FAU - Nyati, Kishan K AU - Nyati KK AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Masuda, Kazuya AU - Masuda K AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Zaman, Mohammad Mahabub-Uz AU - Zaman MM AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Dubey, Praveen K AU - Dubey PK AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Millrine, David AU - Millrine D AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Chalise, Jaya P AU - Chalise JP AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Higa, Mitsuru AU - Higa M AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Li, Songling AU - Li S AD - Laboratory of System Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Standley, Daron M AU - Standley DM AD - Laboratory of System Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. FAU - Saito, Kazunobu AU - Saito K AD - Central Instrumentation Laboratory, Research Institute of Microbial Diseases, Osaka University, Osaka 565-0871, Japan. FAU - Hanieh, Hamza AU - Hanieh H AD - Biological Sciences Department, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia. FAU - Kishimoto, Tadamitsu AU - Kishimoto T AD - Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. LA - eng PT - Journal Article PL - England TA - Nucleic Acids Res JT - Nucleic acids research JID - 0411011 RN - 0 (3' Untranslated Regions) RN - 0 (Arid5a protein, mouse) RN - 0 (DNA-Binding Proteins) RN - 0 (Heterogeneous Nuclear Ribonucleoprotein D0) RN - 0 (Heterogeneous-Nuclear Ribonucleoprotein D) RN - 0 (Hnrpd protein, mouse) RN - 0 (Interleukin-6) RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 0 (Transcription Factors) RN - 0 (interleukin-6, mouse) RN - EC 2.3.2.26 (WWP1 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.1.3.48 (Dual Specificity Phosphatase 1) SB - IM MH - 3' Untranslated Regions MH - Animals MH - Cells, Cultured MH - DNA-Binding Proteins/biosynthesis/genetics/*metabolism MH - Dual Specificity Phosphatase 1/metabolism MH - Heterogeneous Nuclear Ribonucleoprotein D0 MH - Heterogeneous-Nuclear Ribonucleoprotein D/metabolism MH - Interleukin-6/*genetics/metabolism MH - *MAP Kinase Signaling System MH - Mice MH - Mice, Inbred C57BL MH - NF-kappa B/*metabolism MH - *RNA Stability MH - RNA, Messenger/metabolism MH - STAT3 Transcription Factor/metabolism MH - Toll-Like Receptor 4/*metabolism MH - Transcription Factors/biosynthesis/genetics/*metabolism MH - Ubiquitin-Protein Ligases/metabolism MH - Ubiquitination MH - Up-Regulation MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC5389518 EDAT- 2017/02/09 06:00 MHDA- 2017/08/09 06:00 PMCR- 2017/02/07 CRDT- 2017/02/08 06:00 PHST- 2016/09/10 00:00 [received] PHST- 2017/02/06 00:00 [accepted] PHST- 2017/02/09 06:00 [pubmed] PHST- 2017/08/09 06:00 [medline] PHST- 2017/02/08 06:00 [entrez] PHST- 2017/02/07 00:00 [pmc-release] AID - 2972662 [pii] AID - gkx064 [pii] AID - 10.1093/nar/gkx064 [doi] PST - ppublish SO - Nucleic Acids Res. 2017 Mar 17;45(5):2687-2703. doi: 10.1093/nar/gkx064.