Journal article
Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia
The Journal of experimental medicine, Vol.217(4), e20182091
04/06/2020
DOI: 10.1084/jem.20182091
PMCID: PMC7144527
PMID: 31999304
Abstract
Hyper-activation of NLRP3 inflammasomes contributes to the development of endotoxemia, but the molecular mechanisms are poorly defined. Tang et al. demonstrate that sequential ubiquitination of NLRP3 is crucial to keep NLRP3 inflammasomes in check and limits endotoxemia.
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.
Details
- Title: Subtitle
- Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia
- Creators
- Juan Tang - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHSha Tu - University of IowaGuoxin Lin - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHHui Guo - University of Iowa, PathologyChengkai Yan - University of IowaQingjun Liu - The Ohio State UniversityLing Huang - Department of Pathology, University of Iowa, Iowa City, IANa Tang - Hunan Normal UniversityYizhi Xiao - University of IowaR. Marshall Pope - University of Iowa, Medicine AdministrationMurugesan V.S Rajaram - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHAmal O Amer - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHBrian M Ahmer - The Ohio State UniversityJohn S Gunn - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHDaniel J Wozniak - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHLijian Tao - Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaVincenzo Coppola - Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OHLiwen Zhang - The Ohio State UniversityWallace Y Langdon - School of Biomedical Science, University of Western Australia, Perth, AustraliaStanley Lipkowitz - Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDJordi B Torrelles - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OHJian Zhang - University of Iowa, Pathology
- Resource Type
- Journal article
- Publication Details
- The Journal of experimental medicine, Vol.217(4), e20182091
- Publisher
- Rockefeller University Press
- DOI
- 10.1084/jem.20182091
- PMID
- 31999304
- PMCID
- PMC7144527
- ISSN
- 0022-1007
- eISSN
- 1540-9538
- Grant note
- ; R01 AI090901; R01 AI121196; R01 AI123253; R21 AI117547 / ; 16GRNT26990004 / ;
- Alternative title
- Sequential NLRP3 ubiquitination by E3 ligases
- Language
- English
- Date published
- 04/06/2020
- Academic Unit
- Pathology; Medicine Administration
- Record Identifier
- 9984195952902771
Metrics
31 Record Views