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一种由lncRNA Dleu2编码的肽通过促进Smad3介导的调节性T细胞诱导来缓解自身免疫。

A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction.

作者信息

Tang Sibei, Zhang Junxun, Lou Fangzhou, Zhou Hong, Cai Xiaojie, Wang Zhikai, Sun Libo, Sun Yang, Li Xiangxiao, Fan Li, Li Yan, Jin Xinping, Deng Siyu, Yin Qianqian, Bai Jing, Wang Hong, Wang Honglin

机构信息

Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201610, China.

Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

出版信息

EMBO Rep. 2024 Mar;25(3):1208-1232. doi: 10.1038/s44319-024-00070-4. Epub 2024 Jan 30.

DOI:10.1038/s44319-024-00070-4
PMID:38291338
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10933344/
Abstract

Micropeptides encoded by short open reading frames (sORFs) within long noncoding RNAs (lncRNAs) are beginning to be discovered and characterized as regulators of biological and pathological processes. Here, we find that lncRNA Dleu2 encodes a 17-amino-acid micropeptide, which we name Dleu2-17aa, that is abundantly expressed in T cells. Dleu2-17aa promotes inducible regulatory T (iTreg) cell generation by interacting with SMAD Family Member 3 (Smad3) and enhancing its binding to the Foxp3 conserved non-coding DNA sequence 1 (CNS1) region. Importantly, the genetic deletion of Dleu2-17aa in mice by start codon mutation impairs iTreg generation and worsens experimental autoimmune encephalomyelitis (EAE). Conversely, the exogenous supplementation of Dleu2-17aa relieves EAE. Our findings demonstrate an indispensable role of Dleu2-17aa in maintaining immune homeostasis and suggest therapeutic applications for this peptide in treating autoimmune diseases.

摘要

长链非编码RNA（lncRNA）中的短开放阅读框（sORF）编码的微小肽开始被发现并被表征为生物和病理过程的调节因子。在这里，我们发现lncRNA Dleu2编码一种17个氨基酸的微小肽，我们将其命名为Dleu2-17aa，它在T细胞中大量表达。Dleu2-17aa通过与SMAD家族成员3（Smad3）相互作用并增强其与Foxp3保守非编码DNA序列1（CNS1）区域的结合来促进诱导性调节性T（iTreg）细胞的生成。重要的是，通过起始密码子突变在小鼠中对Dleu2-17aa进行基因敲除会损害iTreg的生成并加重实验性自身免疫性脑脊髓炎（EAE）。相反，外源性补充Dleu2-17aa可缓解EAE。我们的研究结果证明了Dleu2-17aa在维持免疫稳态中的不可或缺的作用，并表明该肽在治疗自身免疫性疾病方面的治疗应用。

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