Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 35, Pages 14128-14133Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1205246109
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Funding
- Chinese Ministry of Science and Technology [2012CB910201, 2010DFA31100]
- National Science Foundation of China [91029302, 30921001]
- Chinese 111 Project [B06018]
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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-kappa 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 beta-induced NF-kappa B- and MAPK-activation pathways. Overexpression of MARCH8 inhibits IL-1 beta-induced NF-kappa 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 beta-induced signaling pathways.
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