TY - JOUR AU - Zhang, Yu AU - Liu, Rong-bei AU - Cao, Qian AU - Fan, Ke-qi AU - Huang, Ling-jie AU - Yu, Jian-shuai AU - Gao, Zheng-jun AU - Huang, Tao AU - Zhong, Jiang-yan AU - Mao, Xin-tao AU - Wang, Fei AU - Xiao, Peng AU - Zhao, Yuan AU - Feng, Xin-hua AU - Li, Yi-yuan AU - Jin, Jin T1 - USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance PY - 2019/07/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI123801 VL - 129 IS - 7 UR - https://doi.org/10.1172/JCI123801 SP - 2856 EP - 2871 PB - The American Society for Clinical Investigation ER -