RNF167‐mediated ubiquitination of Tollip inhibits TNF‐α‐triggered NF‐κB and MAPK activation

Abstract

AbstractToll‐interacting protein (Tollip) is a multifunctional regulator in cellular activities. However, whether its functions are subjected to post‐translational modifications remains elusive. Here, we identified ubiquitination as a post‐translational modification on Tollip. We found that Tollip interacted with ring finger protein 167 (RNF167) through its C‐terminal coupling of ubiquitin to ER degradation (CUE) domain, and RNF167 functioned as the potential E3 ligase to attach K33‐linked poly‐ubiquitin chains to the Lys235 (K235) site of Tollip. Furthermore, we discovered Tollip could inhibit TNF‐α‐induced nuclear factor‐kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) activation, and substitution of Lys235 on Tollip to arginine failed to suppress TNF‐α‐NF‐κB/MAPK (JNK) cascades, revealing the role of Tollip and its ubiquitination in NF‐κB/MAPK pathways. Thus, our study reveals the novel biological function of Tollip and RNF167‐dependent ubiquitination of Tollip in TNF‐α signaling.