Translational control of T cell expansion and autoimmune responses by a non-conventional RNA binding protein 2252845

Abstract

Abstract Introduction Naïve CD4+ T cells respond to antigenic stimulus and rapidly transition into active state by intensifying clonal expansion. To meet the bioenergetic demand for this energy-intensive process, CD4+ T cells modulate their transcriptional and translational regulatory mechanisms and fuel profound increase in protein production. However, unlike the transcriptional control, the translational layer of regulation that is at work and the molecular mechanisms underpinning the translational control in T cells remain elusive. AT-rich interactive domain 5a (ARID5a) is an unconventional RBP that primarily stabilizes the pro-inflammatory mRNA transcripts to drive the progression of autoimmune diseases such as EAE and rheumatoid arthritis. However, it remains completely unexplored whether Arid5a regulates protein synthesis in CD4+ T cells to drive autoimmune T cell-mediated responses. Methods Naive CD4+ T cells were activated from Wildtype and Arid5a-/- mice and the effect of Arid5a depletion on protein translation, proliferation and metabolism in T cells was assessed upon polyclonal CD4+ T cell activation as well as upon challenge with MOG- autoantigen. We used polysome profiling and molecular biology approaches to identify the mechanisms underlying the translational regulation by Arid5a. Results We uncovered that Arid5a associated with translation initiation factors, eIF4G and poly A binding protein (PABP) to enhance the translation efficiency of Myc and drive CD4+ T cell expansion. Despite the central role of mTORC1 in controlling protein synthesis, the translational control-mediated by Arid5a was mTOR-independent, suggesting an underappreciated pathway of translational regulation in CD4+T cells. Deficiency of Arid5a disrupted Myc protein production and MOG autoantigen-specific CD4+ T cell proliferation. Conclusion Our study reveals that Arid5a acts as an mTOR-independent translation facilitator and drives autoimmune CD4+ T cell responses. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)