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

• Published in: EMBO reports 2020-03, Vol.21 (3), p.e48860-n/a
• Main Authors: Xiong, Mei‐Guang, Xu, Zhi‐Sheng, Li, Yu‐Hui, Wang, Su‐Yun, Wang, Yan‐Yi, Ran, Yong
• Format: Article
• Language: English
• Subjects: Activation; Adapter proteins; Adapters; Adaptive immunity; Adaptor Proteins, Signal Transducing - genetics; Animals; Cytokines; EMBO19; EMBO31; EMBO37; Endotoxemia; IL‐1β; Immune response; Immune system; Inflammation; Inflammatory response; Interleukins; Lipopolysaccharides; LPS; Mice; MyD88; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Oligomerization; Pattern recognition; Pattern recognition receptors; Proteins; Receptors; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - metabolism; RNF152; Signal Transduction; Signaling; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism; toll‐like receptor; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201948860

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. Synopsis The adapter protein MyD88 functions downstream of both toll‐like receptors (TLRs) and interleukin‐1 receptor (IL‐1R) to activate inflammatory responses. RNF152 positively regulates TLR/IL‐1R‐mediated signaling by enhancing oligomerization of MyD88. Positive regulation of TLR/IL‐1R‐mediated signaling by RNF152 is independent of its E3 ubiquitin ligase activity. RNF152‐deficient mice show impaired inflammatory responses to LPS challenge compared with wild‐type mice. RNF152 interacts with MyD88 and enhances the oligomerization of MyD88. Graphical Abstract The adapter protein MyD88 functions downstream of both toll‐like receptors (TLRs) and interleukin‐1 receptor (IL‐1R) to activate inflammatory responses. RNF152 positively regulates TLR/IL‐1R‐mediated signaling by enhancing oligomerization of MyD88.