Arid5a stabilizes OX40 mRNA in murine CD4+ T cells by recognizing a stem‐loop structure in its 3′UTR. Issue 4 (5th February 2018)

• Record Type: Journal Article
• Authors: Hanieh, Hamza; Masuda, Kazuya; Metwally, Hozaifa; Chalise, Jaya P.; Mohamed, Maged; Nyati, Kishan K.; Standley, Daron M.; Li, Songling; Higa, Mitsuru; Zaman, Mohammad M.; Kishimoto, Tadamitsu
• Is Part Of: European journal of immunology. Volume 48:Issue 4(2018)
• Page Start: 593
• Page End: 604
• Publication Date: 2018-02-05
• Subjects: Arid5a -- EAE -- IL‐17 -- IL‐6 -- OX40 -- Th17; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747109
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: AT‐rich interactive domain‐containing protein 5a (Arid5a) is an RNA‐binding protein (RBP) required for autoimmunity via stabilization of interleukin‐6 ( Il6 ) and signal transducer and activator of transcription 3 ( STAT3 ) mRNAs. However, the roles of Arid5a in Th17 cells and its association with autoimmunity remain unknown. Here, we show that the levels of Arid5a and OX40 are correlated in CD4 + T cells under Th17 conditions in an IL‐6‐dependent manner. Lack of Arid5a in T cells reduced OX40 expression levels and repressed IL‐17 production in response to OX40 ligation. Arid5a stabilized OX40 mRNA by recognizing the alternative decay element (ADE)‐like stem‐loop (SL) in the 3′ untranslated region (3′UTR). Interestingly, Arid5a impaired the RNA‐destabilizing functions of Regnase‐1 and Roquin‐1 on OX40 ADE‐like SL. In EAE, Arid5a‐deficient mice exhibited resistance to EAE, with reduced OX40 expression in CD4 + T cells, and the number of CD4 + CD45 + T cells was decreased in CNS. Furthermore, ameliorated EAE was induced by adoptive transfer of Arid5a −/− encephalitogenic CD4 + T cells expressing less OX40 mRNA and producing less IL‐17. In conclusion, our findings indicate that the Arid5a/OX40 axis in CD4 + T cells may have important implications in pathogenesis of autoimmune diseases such as EAE. Abstract : Arid5a stabilizes STAT3 and OX40 mRNAs under Th17‐conditions (IL‐6 and TGF‐β) by recognizing stem‐loop (SL) structures in their 3′UTR. Binding of Arid5a to these SLs physically prevents Regnase‐1/Roquin‐1 from binding to the loop elements and impairs their RNA‐destabilizing functions. In addition, STAT3 plays direct/indirect enhancing roles on OX40 expression.