RNF152 positively regulates TLR/IL‐1R signaling by enhancing MyD88 oligomerization

摘要

Toll‐like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL‐1β is an important pro‐inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. TLRs and interleukin‐1 receptor (IL‐1R) share similar cytosolic domains and signaling processes. In this study, we identify the E3 ubiquitin ligase RNF152 as a positive regulator of TLR/IL‐1R‐mediated signaling. Overexpression of RNF152 potentiates IL‐1β‐ and LPS‐induced NF‐κB activation in an ubiquitination‐independent manner, whereas knockdown of RNF152 has the opposite effects. RNF152‐deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS‐induced lethal endotoxemia. Mechanistically, RNF152 interacts with the adaptor protein MyD88 and enhances oligomerization of MyD88, which is essential for the recruitment of downstream signaling components and activation of TLR/IL‐1R‐mediated signal transduction. Our findings suggest that RNF152‐mediated oligomerization of MyD88 is important for TLR/IL‐1R‐mediated inflammatory response.