The E3 ubiquitin ligase MARCH8 negatively regulates IL-1?-induced NF-?B activation by targeting the IL1RAP coreceptor for ubiquitination and degradation.

ABSTRACT: The proinflammatory cytokine interleukin-1 (IL-1) signals via type I IL-1 receptor (IL-1RI) and IL-1 receptor accessory protein (IL1RAP), which leads to activation of the transcription factor NF-?B and induction of a range of downstream proteins involved in inflammatory and immune responses. Here, we identified the E3 ubiquitin ligase membrane-associated RING-CH (MARCH8) as a suppressor of IL-1?-induced NF-?B- and MAPK-activation pathways. Overexpression of MARCH8 inhibits IL-1?-induced NF-?B and MAPK activation, whereas knockdown of MARCH8 has the opposite effect. Mechanistically, MARCH8 interacts with IL1RAP and targets its Lys512 for K48-linked polyubiquitination and degradation. Our findings suggest that MARCH8-mediated polyubiquitination and degradation of IL1RAP is an important mechanism for negative regulation of IL-1?-induced signaling pathways.

SUBMITTER: Chen R 

PROVIDER: S-EPMC3435212 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature