Publication: The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation.

Published in: Nat Commun 2017 Jun; 8(): 15502

Authors: Lee CY, Lai TY, Tsai MK, Chang YC, Ho YH, Yu IS, Yeh TW, Chou CC, Lin YS, Lawrence T, Hsu LC

Summary

Caveolin-1 (CAV1), the major constituent of caveolae, plays a pivotal role in various cellular biological functions, including cancer and inflammation. The ubiquitin/proteasomal pathway is known to contribute to the regulation of CAV1 expression, but the ubiquitin ligase responsible for CAV1 protein stability remains unidentified. Here we reveal that E3 ubiquitin ligase ZNRF1 modulates CAV1 protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses. We demonstrate that ZNRF1 physically interacts with CAV1 in response to lipopolysaccharide and mediates ubiquitination and degradation of CAV1. The ZNRF1-CAV1 axis regulates Akt-GSK3β activity upon TLR4 activation, resulting in enhanced production of pro-inflammatory cytokines and inhibition of anti-inflammatory cytokine IL-10. Mice with deletion of ZNRF1 in their hematopoietic cells display increased resistance to endotoxic and polymicrobial septic shock due to attenuated inflammation. Our study defines ZNRF1 as a regulator of TLR4-induced inflammatory responses and reveals another mechanism for the regulation of TLR4 signalling through CAV1.

Link to Pubmed [PMID] – 28593998

Link to HAL – hal-04132654

Link to DOI – 10.1038/ncomms15502