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Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14128-33. doi: 10.1073/pnas.1205246109. Epub 2012 Aug 16.

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

Author information

1
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.

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-κB 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-1β-induced NF-κB- and MAPK-activation pathways. Overexpression of MARCH8 inhibits IL-1β-induced NF-κB 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-1β-induced signaling pathways.

PMID:
22904187
PMCID:
PMC3435212
DOI:
10.1073/pnas.1205246109
[Indexed for MEDLINE]
Free PMC Article

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