中国医学科学院曹雪涛研究小组报道了RNA结合E3连接酶MKRN2选择性地破坏Il-6的翻译以抑制炎症。2025年6月16日出版的《自然—免疫学》发表了这项成果。

本研究发现，RNA结合E3连接酶MKRN2选择性抑制脂多糖活化巨噬细胞中白细胞介素-6 （IL-6）的表达。LysM-Cre⁺Mkrn2^fl/fl小鼠在脂多糖处理后血清中IL-6含量增加，实验性结肠炎严重程度增加，这与IL-6升高有关。在溃疡性结肠炎和类风湿关节炎患者的临床样本中，MKRN2的表达与IL-6的表达呈负相关。机制上，在与Il6信使RNA结合后，MKRN2将K29多泛素链连接到Lys翻译起始辅激活因子PAIP1的179个残基阻断了PAIP1–eIF4A的相互作用并抑制了Il6 mRNA的翻译效率。他们的发现通过破坏特定促炎细胞因子的翻译，为炎症性自身免疫性疾病提供了机制见解和潜在的治疗策略。

据介绍，E3连接酶和RNA结合蛋白介导的促炎细胞因子失调导致自身免疫性和炎症性疾病。然而，RNA结合的E3连接酶是否可以调节特异性促炎细胞因子的表达尚不清楚。

附：英文原文

Title: The RNA-binding E3 ligase MKRN2 selectively disrupts Il6 translation to restrain inflammation

Author: Yu, Zhou, Li, Xuelian, Huang, Jiaying, Pan, Jueyu, Cheng, Jiale, Liu, Ping, Yang, Mingjin, Chen, Taoyong, Zhang, Qian, Zhou, Yumei, Wu, Jiacheng, Han, Taotao, Li, Jingnan, Xu, Yue, Wen, Mingyue, Zhang, Xuan, Wang, Chunmei, Cao, Xuetao

Issue&Volume: 2025-06-16

Abstract: E3 ligases and RNA-binding protein-mediated dysregulation of proinflammatory cytokines leads to autoimmune and inflammatory diseases. However, whether RNA-binding E3 ligases can regulate specific proinflammatory cytokine expression remains unclear. Here we found that the RNA-binding E3 ligase MKRN2 selectively inhibits the expression of interleukin-6 (IL-6) in lipopolysaccharide-activated macrophages. LysM-Cre+Mkrn2fl/fl mice showed increased amounts of IL-6 in the serum after lipopolysaccharide treatment and exhibited increased severity of experimental colitis, which was associated with increased IL-6. Expression of MKRN2 negatively correlated with expression of IL-6 in clinical samples from individuals with ulcerative colitis and rheumatoid arthritis. Mechanistically, after binding to Il6 messenger RNA, MKRN2 linked K29 polyubiquitin chains to the Lys179 residue of PAIP1, a translation initiation coactivator, which blocked PAIP1–eIF4A interaction and thus inhibited the translational efficiency of Il6 mRNA. Our findings provide mechanistic insight and potential therapeutic strategies for inflammatory autoimmune diseases by disrupting translation of specific proinflammatory cytokines.

DOI: 10.1038/s41590-025-02183-x

Source: https://www.nature.com/articles/s41590-025-02183-x