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- Title
USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance.
- Authors
Yu Zhang; Rong-bei Liu; Qian Cao; Ke-qi Fan; Ling-jie Huang; Jian-shuai Yu; Zheng-jun Gao; Tao Huang; Jiang-yan Zhong; Xin-tao Mao; Fei Wang; Peng Xiao; Yuan Zhao; Xin-hua Feng; Yi-yuan Li; Jin Jin; Zhang, Yu; Liu, Rong-Bei; Cao, Qian; Fan, Ke-Qi
- Abstract
Calcineurin acts as a calcium-activated phosphatase that dephosphorylates various substrates, including members of the nuclear factor of activated T cells (NFAT) family, to trigger their nuclear translocation and transcriptional activity. However, the detailed mechanism regulating the recruitment of NFATs to calcineurin remains poorly understood. Here, we report that calcineurin A (CNA), encoded by PPP3CB or PPP3CC, is constitutively ubiquitinated on lysine 327, and this polyubiquitin chain is rapidly removed by ubiquitin carboxyl-terminal hydrolase 16 (USP16) in response to intracellular calcium stimulation. The K29-linked ubiquitination of CNA impairs NFAT recruitment and transcription of NFAT-targeted genes. USP16 deficiency prevents calcium-triggered deubiquitination of CNA in a manner consistent with defective maintenance and proliferation of peripheral T cells. T cell-specific USP16 knockout mice exhibit reduced severity of experimental autoimmune encephalitis and inflammatory bowel disease. Our data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. Notably, our results highlight a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.
- Subjects
T cells; INFLAMMATORY bowel diseases; INTRACELLULAR calcium; CALCINEURIN; KNOCKOUT mice
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 7, p2856
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI123801