The RNA-binding E3 ligase MKRN2 selectively disrupts IL-6 translation to restrain inflammation

Dysregulation of proinflammatory cytokine production leads to autoimmune and inflammatory diseases. Although E3 ligases and RNA-binding proteins (RBPs) are critical in autoimmunity and inflammation, whether RNA-binding E3 ligases (E3-RBPs) can regulate proinflammatory cytokine expression to be involved in autoimmune disorders remains unclear. Here, we found that MKRN2, an E3-RBP, selectively inhibits IL-6 expression in LPS-activated macrophages. MKRN2-deficient mice have increased IL-6 serum levels at the untreated stage or after LPS treatment, and exhibit increased severity of experimental colitis which is associated with increased IL-6 levels. MKRN2 is negatively correlated with IL-6 expression in clinical samples from patients with ulcerative colitis and rheumatoid arthritis. Mechanistically, upon encountering Il6 mRNA, MKRN2 links K29 polyubiquitin to Lys179 of PAIP1 which blocks PAIP1-eIF4A interaction, thus inhibiting the translational efficiency of Il6 mRNA. Our findings provide new mechanistic insight and potential therapeutic strategies for inflammatory autoimmune diseases by disrupting translation process of specific proinflammatory cytokines. Overall design: CLIP-seq of MKRN2 in RAW264.7 cell treated with LPS (100ng/ml) for 8 hours