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

Chen, Rui, Li, Mi, Zhang, Yu, Zhou, Qian, Shu, Hong-Bing
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.35 pp. 14128-14133
immune response, interleukin-1, mitogen-activated protein kinase, proteins, signal transduction, transcription factor NF-kappa B, transcriptional activation, ubiquitin-protein ligase, ubiquitination
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.