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

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

Mei-Guang Xiong , Zhi-Sheng Xu, Yu-Hui Li, Su-Yun Wang , Yan-Yi Wang, Yong Ran

EMBO REPORTS，卷: 21  期: 3，文献号: e48860，DOI: 10.15252/embr.201948860

Abstract

Toll-like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL-1 beta 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-1 beta- and LPS-induced NF-kappa B 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.