Identification of a Long Noncoding RNA TRAF3IP2-AS1 as Key Regulator of IL-17 Signaling through the SRSF10-IRF1-Act1 Axis in Autoimmune Diseases
Identification of a Long Noncoding RNA TRAF3IP2-AS1 as Key Regulator of IL-17 Signaling through the SRSF10-IRF1-Act1 Axis in Autoimmune Diseases
复制标题
鉴定长非编码 RNA TRAF3IP2-AS1 作为自身免疫性疾病中通过 SRSF10-IRF1-Act1 轴的 IL-17 信号传导的关键调节剂。
DOI：
10.4049/jimmunol.2001223
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发表时间：
2021-05-15
影响因子：
4.4
通讯作者：
Wang, Chenhui
中科院分区：
文献类型：
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作者：
He, Ruirui;Wu, Songfang;Wang, Chenhui
IL-17 A在许多自身免疫性疾病的发病机制中起重要作用，包括银屑病和多发性硬化症。Act 1是IL-17 A信号通路中的关键衔接子。在这项研究中，我们报告了一个反义长非编码RNA，TRAF 3 IP 2-AS 1，调节Act 1的表达和IL-17 A信号通过招募SRSF 10，下调IRF 1，Act 1的转录因子的表达。有趣的是，我们发现TRAF 3 IP 2-AS 1 A4165 G（rs 13210247）的银屑病易感变体是功能获得性突变体。此外，我们鉴定了小鼠基因E130307 A14-Rik，其与TRAF 3 IP 2-AS 1同源，并且具有类似的调节Act 1表达和IL-17 A信号传导的能力。重要的是，用表达E130307 A14-Rik或SRSF 10的慢病毒治疗在银屑病和实验性自身免疫性脑脊髓炎的小鼠模型中产生了治疗效果。这些发现表明TRAF 3 IP 2-AS 1和/或SRSF 10可能代表治疗IL-17相关自身免疫性疾病（如银屑病和多发性硬化症）的有吸引力的治疗靶点。
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, TRAF3IP2-AS1, 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 TRAF3IP2-AS1 A4165G (rs13210247) is a gain-of-function mutant. Furthermore, we identified a mouse gene E130307A14-Rik that is homologous to TRAF3IP2-AS1 and has a similar ability to regulate Act1 expression and IL-17A signaling. Importantly, treatment with lentiviruses expressing E130307A14-Rik or SRSF10 yielded therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis. These findings suggest that TRAF3IP2-AS1 and/or SRSF10 may represent attractive therapeutic targets in the treatment of IL-17-related autoimmune diseases, such as psoriasis and multiple sclerosis.