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

Chih-Yuan Lee, Ting-Yu Lai, Meng-Kun Tsai, Yung-Chi Chang, Yu-Hsin Ho, I-Shing Yu, Tzu-Wen Yeh, Chih-Chang Chou, You-Sheng Lin, Toby Lawrence and Li-Chung Hsu ()
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Chih-Yuan Lee: Institute of Molecular Medicine, National Taiwan University
Ting-Yu Lai: Institute of Molecular Medicine, National Taiwan University
Meng-Kun Tsai: National Taiwan University Hospital
Yung-Chi Chang: Institute of Molecular Medicine, National Taiwan University
Yu-Hsin Ho: Institute of Molecular Medicine, National Taiwan University
I-Shing Yu: Laboratory Animal Center, College of Medicine, National Taiwan University
Tzu-Wen Yeh: Institute of Molecular Medicine, National Taiwan University
Chih-Chang Chou: Institute of Molecular Medicine, National Taiwan University
You-Sheng Lin: Institute of Molecular Medicine, National Taiwan University
Toby Lawrence: Institut National de la Santé et de la Recherche Médicale (INSERM), U1104
Li-Chung Hsu: Institute of Molecular Medicine, National Taiwan University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15502

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