期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 217, 期 4, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20182091
关键词
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资金
- Carver Foundation
- Howard Hughes Medical Institute
- US National Institutes of Health [R01 AI090901, R01 AI121196, R01 AI123253, R21 AI117547]
- American Heart Association [16GRNT26990004]
- NATIONAL CANCER INSTITUTE [ZIABC010977] Funding Source: NIH RePORTER
Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3-dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.
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