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

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

doi:10.1038/s41590-025-02183-x

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

Nat Immunol. 2025 Jun 16. doi: 10.1038/s41590-025-02183-x. Online ahead of print.

Authors

Zhou Yu^#^{1

2

3}, Xuelian Li^#⁴, Jiaying Huang⁵, Jueyu Pan⁴, Jiale Cheng⁴, Ping Liu⁴, Mingjin Yang⁵, Taoyong Chen⁵, Qian Zhang⁵, Yumei Zhou^{4

6}, Jiacheng Wu⁶, Taotao Han⁷, Jingnan Li⁷, Yue Xu⁸, Mingyue Wen^{4

6}, Xuan Zhang⁸, Chunmei Wang^{4

6}, Xuetao Cao^{9

10

11

12}

Affiliations

¹ National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China. yz@ism.cams.cn.
² Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. yz@ism.cams.cn.
³ Institute of Immunology, Naval Medical University, Shanghai, China. yz@ism.cams.cn.
⁴ National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
⁵ Institute of Immunology, Naval Medical University, Shanghai, China.
⁶ Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
⁷ Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
⁸ Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
⁹ National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China. caoxt@immunol.org.
¹⁰ Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. caoxt@immunol.org.
¹¹ Institute of Immunology, Naval Medical University, Shanghai, China. caoxt@immunol.org.
¹² Institute of Immunology, College of Life Science, Nankai University, Tianjin, China. caoxt@immunol.org.

^# Contributed equally.

PMID: 40524017
DOI: 10.1038/s41590-025-02183-x

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⁺Mkrn2^fl/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 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.

Abstract

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