(Correspondent He Ruirui) on May 6, Professor Wang Chenhui's team of School of Life Science, Huazhong University of Science and Technology published a research paper entitled "identification of a long noncoding RNA TRAF3IP2-AS1 as key regulator of IL-17 signaling through the srsf10-irf1-act1 axis in autoimmune diseases" in the international authoritative The Journal of Immunology.
Link to the paper: https://pubmed.ncbi.nlm.nih.gov/33941656/
Autoimmune diseases are caused by the body's immune response to its own tissues and organs, which results in tissue damage. Common autoimmune diseases include multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis and systemic lupus erythematosus. In recent years, more and more evidence shows that Th17 cell differentiation defects or IL-17 signaling pathway abnormalities mediate a variety of autoimmune diseases. Genome wide association study (GWAS) data show that there is a relationship between single nucleotide polymorphisms of many genes and susceptibility to autoimmune diseases. It has been found that the variation of long noncoding RNA (LncRNA) TRAF3IP2-AS1 is associated with the susceptibility of psoriasis, but the molecular mechanism of this molecule contributing to susceptibility of psoriasis is still unclear. Exploring the molecular mechanism of its involvement in the occurrence of autoimmune diseases is of great significance for understanding the occurrence of diseases and exploring the treatment clues of diseases.
In human body, Th17 cells are mainly responsible for the distinguish of fungal infection by secreting IL-17. But IL-17 is also an inflammatory cytokines, which promotes inflammation by mediating the activation of IL-17 signaling pathway. Therefore, the abnormal IL-17 signaling pathway is closely related to the occurrence and development of a variety of autoimmune diseases. As an important adaptor protein in IL-17 signaling pathway, the mutation of TRAF3IP2 (coding protein is ACT1) is also closely related to the occurrence of many autoimmune diseases. It is reported that a single nucleotide mutation (rs13210247) in the intron region of the TRAF3IP2 gene is significantly related to the susceptibility of human psoriasis. The variance is located in exon 4 of antisense LncRNA TRAF3IP2-AS1 of TRAF3IP2 (TRAF3IP2-AS1 A4165G). In this study, we found that TRAF3IP2-AS1 inhibited the expression of ACT1 transcription factor IRF1 by recruiting SRSF10, and then decreased the expressional level of ACT1 and inhibited the activation of IL-17 signaling pathway. We also found that the single nucleotide mutation rs13210247 (A4165G) of TRAF3IP2-AS1 is a gain-of-function variant, which inhibit the expression of ACT1 and the activation of IL-17 signaling pathway by enhancing the binding with SRSF10. In addition, we found that LncRNA E130307A14 Rik in mice is a homologous gene of human TRAF3IP2-AS1, which can also inhibit the expression of ACT1 and the activation of IL-17 signaling pathway in mice. The results showed that the E130307A14 Rik or SRSF10 expressed by retrovirus could significantly alleviate the symptoms of psoriasis and experimental autoimmune encephalomyelitis in mice. It suggested that TRAF3IP2-AS1 and SRSF10 could be used as potential targets and means for the treatment of psoriasis and multiple sclerosis. In conclusion, this study not only systematically elucidates the molecular mechanism of LncRNA TRAF3IP2-AS1 in the development of autoimmune diseases, but also further indicates that TRAF3IP2-AS1 and SRSF10 can be used as potential targets for the treatment of autoimmune diseases related to Th17 cells, such as psoriasis and multiple sclerosis.
Dr. He Ruirui, PhD student, Gao Ru, PhD student and Dr. Wu Songfang of Xuhui Central Hospital of Fudan University are the co first authors of the paper. Professor Wang Yueying of Ruijin Hospital, Shanghai Jiaotong University, Professor Zhang Cun-jin of Nanjing University and Professor Wang Chenhui of Huazhong University of science and technology are the co-correspondence authors of this paper. This research is supported by the National Natural Science Fund of China and National Natural Science Fund of Shanghai.
