TRIM14 Promotes Noncanonical NF-?B Activation by Modulating p100/p52 Stability via Selective Autophagy.

ABSTRACT: The noncanonical NF-?B signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-?B signaling largely relies on the abundance as well as the processing of the NF-?B family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-?B signaling pathway. TRIM14 promotes noncanonical NF-?B activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-?B-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-?B signaling and highlight the crosstalk between autophagy and innate immunity.

SUBMITTER: Chen M 

PROVIDER: S-EPMC6947505 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature