USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance
Yu Zhang, … , Yi-yuan Li, Jin Jin
Yu Zhang, … , Yi-yuan Li, Jin Jin
Published May 28, 2019
Citation Information: J Clin Invest. 2019;129(7):2856-2871. https://doi.org/10.1172/JCI123801.
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Research Article Cell biology Immunology

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance

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.

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

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Figure 8

USP16 deficiency in T cells impairs CNS inflammation.

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USP16 deficiency in T cells impairs CNS inflammation. (A) Box plot of US...
(A) Box plot of USP16 expression in multiple sclerosis (MS) patients (using public data set GDS3920; n = 27). (B) Clinical scores of 6- to 8-week-old WT and USP16-KO mice (female, n = 15 per group) after the induction of experimental autoimmune encephalomyelitis (EAE) with MOG35–55. (C) H&E staining of spinal cord sections on day 30. Scale bar: 500 μm. (D) FACS analyses and summary of immune cell infiltration into the brain and spinal cord of mice with EAE (n = 4, day 14 postimmunization). (E and F) Proliferation and cytokine secretion of splenic T cells from mice with EAE stimulated in vitro with MOG35–55 (10 μg/ml) were measured by CCK8 assay and ELISA, respectively, on day 15. Data are representative of 3 independent experiments with 3 mice in each group (C–F), and 2 experiments with 15 mice each group (B).The error bars show the mean ± SEM. The significance of difference in B was determined by Sidak’s multiple comparisons test. The significances of differences in all other 2-group comparisons were determined by 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.