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

Ruirui He; Songfang Wu; Ru Gao; Jianwen Chen; Qianwen Peng; Huijun Hu; Liwen Zhu; Yanyun Du; Wanwei Sun; Xiaojian Ma; Huazhi Zhang; Zhihui Cui; Heping Wang; Bradley N Martin; Yueying Wang; Cun-Jin Zhang; Chenhui Wang

doi:10.4049/jimmunol.2001223

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

J Immunol. 2021 May 15;206(10):2353-2365. doi: 10.4049/jimmunol.2001223. Epub 2021 May 3.

Authors

Ruirui He¹, Songfang Wu^{2

3}, Ru Gao¹, Jianwen Chen¹, Qianwen Peng¹, Huijun Hu¹, Liwen Zhu⁴, Yanyun Du¹, Wanwei Sun¹, Xiaojian Ma¹, Huazhi Zhang¹, Zhihui Cui¹, Heping Wang¹, Bradley N Martin³, Yueying Wang⁵, Cun-Jin Zhang⁶, Chenhui Wang^{7

8}

Affiliations

¹ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
² Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital, Fudan University, Shanghai, People's Republic of China.
³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
⁴ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
⁵ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China [email protected] [email protected] [email protected].
⁶ Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China [email protected] [email protected] [email protected].
⁷ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China [email protected] [email protected] [email protected].
⁸ Wuhan Institute of Biotechnology, Wuhan, China.

PMID: 33941656
DOI: 10.4049/jimmunol.2001223

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, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Encephalomyelitis, Autoimmune, Experimental / metabolism*
Gene Knockout Techniques
HaCaT Cells
HeLa Cells
Humans
Interferon Regulatory Factor-1 / metabolism*
Interleukin-17 / metabolism*
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Psoriasis / metabolism*
RNA / genetics
RNA / metabolism*
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Serine-Arginine Splicing Factors / genetics
Serine-Arginine Splicing Factors / metabolism*
Signal Transduction / genetics*
Transfection

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
IL17A protein, human
IRF1 protein, human
Il17a protein, mouse
Interferon Regulatory Factor-1
Interleukin-17
Irf1 protein, mouse
RNA, Long Noncoding
Repressor Proteins
SRSF10 protein, human
SRSF10 protein, mouse
TRAF3IP2 protein, human
TRAF3IP2-AS1 antisense RNA, human
Traf3ip2 protein, mouse
Serine-Arginine Splicing Factors
RNA