Other
22 Authors
- Gunn JS,
- Tu S,
- Coppola V,
- Torrelles JB,
- Zhang J,
- Guo H,
- Lin G,
- Tang J,
- Wozniak DJ,
- Ahmer BM,
- Pope RM,
- Zhang L,
- Tao L,
- Amer AO,
- Liu Q,
- Yan C,
- Tang N,
- Lipkowitz S,
- Rajaram MVS,
- Langdon WY,
- Huang L,
- Xiao Y
| First Author | Tang J | Year | 2020 |
| Journal | J Exp Med | Volume | 217 |
| Issue | 4 | PubMed ID | 31999304 |
| Mgi Jnum | J:287280 | Mgi Id | MGI:6415848 |
| Doi | 10.1084/jem.20182091 | Citation | Tang J, et al. (2020) Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia. J Exp Med 217(4) |
| abstractText | 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. |
