3 years ago

The N-terminal ubiquitin-associated domain of Cezanne is crucial for its function to suppress NF-κB pathway

Deyin Guo, Qiaoqiao Xiao, Zhen Zhang, Lanyi Zeng, Liu Cao, Yanxi Ji, Shiyou Chen, Penglin Guan, Yu Chen, Min Wang
Cezanne, a deubiquitinating cysteine protease (DUB) belonging to A20 subgroup of ovarian tumor (OTU) protein superfamily, functions as a negative regulator of NF-κB to attenuate NF-κB activation and to restrain pro-inflammatory transcription in response to TNF receptor (TNFR) signaling. It is the first documented OTU DUB that preferably disassembles Lys11-linked polyubiquitin chains and has been shown to regulate multiple cellular events including immune signaling, cell survival and tumor progression. Previous studies showed that in response to TNF stimulation, Cezanne is recruited to the activated TNFR complex to suppress the build-up of polyubiquitinated RIP1 signal by removing Lys63 polyubiquitin from RIP1. However, how is Cezanne recognized and recruited to TNFR complex is not clear yet. In this study, we characterized a ubiquitin-associated (UBA) domain in the N-terminal region of Cezanne and proved its activity to bind Lys63 polyubiquitin chain. By constructing a series of truncated and site-specific point mutants, we further localized the crucial binding sites for Lys63 polyubiquitin chains at Leu9 and Ser10 sites of Cezanne UBA domain. Mutation at these sites disrupted the recruitment of Cezanne to activated TNFR complex and dramatically reduced the inhibition of NF-κB activation by Cezanne. Our study demonstrated that the N-terminal UBA domain is crucial for the function of Cezanne during NF-κB activation. Cezanne is recognized and recruited into activated TNFR complex by specifically binding to polyubiquitinated signaling proteins after TNF stimulation through its N-terminal polyubiquitin binding site. This study sheds light on the molecular mechanism of negative regulation of NF-κB activation by Cezanne.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/jcb.26359

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