| First Author | Zhang Y | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 7 | Pages | 2856-2871 |
| PubMed ID | 31135381 | Mgi Jnum | J:289349 |
| Mgi Id | MGI:6435030 | Doi | 10.1172/JCI123801 |
| Citation | Zhang Y, et al. (2019) USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance. J Clin Invest 129(7):2856-2871 |
| abstractText | 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. |
