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
National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Nat Immunol. 2025 Jun 16. doi: 10.1038/s41590-025-02183-x.
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-CreMkrn2 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 Lys 179 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.
E3 连接酶和 RNA 结合蛋白介导的促炎细胞因子失调会导致自身免疫性疾病和炎症性疾病。然而，RNA 结合 E3 连接酶是否能够调节特定促炎细胞因子的表达仍不清楚。在此，我们发现 RNA 结合 E3 连接酶 MKRN2 在脂多糖激活的巨噬细胞中选择性抑制白细胞介素-6（IL-6）的表达。LysM-CreMkrn2 小鼠在脂多糖处理后血清中 IL-6 含量增加，并表现出实验性结肠炎的严重程度增加，这与 IL-6 增加有关。在溃疡性结肠炎和类风湿性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，MKRN2 与 Il6 信使核糖核酸结合后，将 K29 多聚泛素链连接到翻译起始共激活因子 PAIP1 的 Lys 179 残基上，这阻断了 PAIP1-eIF4A 的相互作用，从而抑制了 Il6 信使核糖核酸的翻译效率。我们的研究结果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性见解和潜在的治疗策略。
