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Updated: Sep 19, 2025

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

Zhou Yu1,2,3, Xuelian Li4, Jiaying Huang5

  • 1National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China. yz@ism.cams.cn.

Nature Immunology
|June 16, 2025
PubMed

Insights

The RNA-binding E3 ligase MKRN2 inhibits interleukin-6 (IL-6) production in macrophages. This finding offers new therapeutic strategies for inflammatory autoimmune diseases by targeting specific cytokine translation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Dysregulation of proinflammatory cytokines by E3 ligases and RNA-binding proteins contributes to autoimmune and inflammatory diseases.
  • The specific role of RNA-binding E3 ligases in regulating cytokine expression is not well understood.

Purpose of the Study:

  • To investigate whether RNA-binding E3 ligases can regulate specific proinflammatory cytokine expression.
  • To elucidate the mechanism by which MKRN2 affects interleukin-6 (IL-6) expression.

Main Methods:

  • Utilized LysM-Cre+Mkrn2fl/fl mice and lipopolysaccharide (LPS) activation to study IL-6 levels.
  • Analyzed clinical samples from patients with ulcerative colitis and rheumatoid arthritis.
  • Investigated the molecular mechanism involving MKRN2, Il6 messenger RNA (mRNA), and PAIP1 interaction.

Main Results:

  • MKRN2 selectively inhibits IL-6 expression in activated macrophages.
  • Mice lacking MKRN2 exhibited elevated IL-6 and increased severity of experimental colitis.
  • MKRN2 expression inversely correlated with IL-6 in human inflammatory disease samples.
  • MKRN2 polyubiquitinated PAIP1, inhibiting IL-6 mRNA translation.

Conclusions:

  • MKRN2 acts as a negative regulator of IL-6 translation.
  • Targeting MKRN2-mediated translational control offers potential therapeutic strategies for inflammatory autoimmune diseases.

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