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

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 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.