E3 ubiquitin ligase Nedd4 inhibits AP-1 activity and TNF-? production through targeting p38? for polyubiquitination and subsequent degradation.

ABSTRACT: p38? plays an important role in many inflammatory diseases, such as skin inflammation, endotoxic shock and arthritis. Ubiquitination is a vital posttranslational modification of proteins and plays a crucial regulatory role in inflammatory cells. It has been reported that ubiquitination of Tak1 and TAB1 upstream of p38? can regulate p38? activation respectively. However, p38? ubiquitination is not yet clear. In this paper, we showed that E3 ubiquitin ligase Nedd4 is a regulatory component of the p38? pathway and is responsible for polyubiquitination of p38? through K48-linked and K63-linked polyubiquitination. The levels of p38? and its downstream target TNF-? were increased in Nedd4 deficient macrophages response to LPS compared with wild-type cells. AP-1 activity and degradation of p38? were induced by Nedd4 in a dose-dependent manner. Furthermore, we found that phosphorylation of p38? is involved in the interactions between p38? and Nedd4 and subsequently promotes polyubiquitination of p38?, especially K48-linked polyubiquitination by Nedd4. The different conformation of two p38? isoforms (p38?V1 and p38?V2) might be the cause of their different interactions with Nedd4 and their polyubiquitination sites by Nedd4. Thus, NEDD4 is a previously unknown component of the p38? signaling complex necessary for TNF-? activation.

SUBMITTER: Liu Q 

PROVIDER: S-EPMC5495757 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature