Identification of a Long Noncoding RNA <i>TRAF3IP2-AS1</i> as Key Regulator of IL-17 Signaling through the SRSF10–IRF1–Act1 Axis in Autoimmune Diseases

Abstract

IL-17A plays an essential role in the pathogenesis of many autoimmune diseases, including psoriasis and multiple sclerosis. Act1 is a critical adaptor in the IL-17A signaling pathway. In this study, we report that an anti-sense long noncoding RNA, <i>TRAF3IP2-AS1</i>, regulates Act1 expression and IL-17A signaling by recruiting SRSF10, which downregulates the expression of IRF1, a transcriptional factor of Act1. Interestingly, we found that a psoriasis-susceptible variant of <i>TRAF3IP2-AS1</i> A4165G (rs13210247) is a gain-of-function mutant. Furthermore, we identified a mouse gene <i>E130307A14-Rik</i> that is homologous to <i>TRAF3IP2-AS1</i> and has a similar ability to regulate Act1 expression and IL-17A signaling. Importantly, treatment with lentiviruses expressing <i>E130307A14-Rik</i> or SRSF10 yielded therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis. These findings suggest that <i>TRAF3IP2-AS1</i> and/or SRSF10 may represent attractive therapeutic targets in the treatment of IL-17-related autoimmune diseases, such as psoriasis and multiple sclerosis.