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

Zhang, Y;Liu, RB;Cao, Q;Fan, KQ;Huang, LJ;Yu, JS;Gao, ZJ;Huang, T;Zhong, JY;Mao, XT;Wang, F;Xiao, P;Zhao, Y;Feng, XH;Li, YY;Jin, J;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

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.

PubMed ID: 31135381
357135712019-06-172019-06-1714:32:1914:32:192019-06-252019-06-2514:28:0614:28:06Zhang, Y;Liu, RB;Cao, Q;Fan, KQ;Huang, LJ;Yu, JS;Gao, ZJ;Huang, T;Zhong, JY;Mao, XT;Wang, F;Xiao, P;Zhao, Y;Feng, XH;Li, YY;Jin, J;Zhang, Y;Liu, RB;Cao, Q;Fan, KQ;Huang, LJ;Yu, JS;Gao, ZJ;Huang, T;Zhong, JY;Mao, XT;Wang, F;Xiao, P;Zhao, Y;Feng, XH;Li, YY;Jin, J;20192019USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenanceUSP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenanceThe Journal Of Clinical InvestigationThe Journal Of Clinical Investigation1301303113538131135381

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.

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.

12.812.8

Induction and assessment of EAE:

For active EAE induction, age- and sex-matched mice were immunized s.c. with MOG35-55 peptide (300 μg) mixed in CFA (Sigma-Aldrich) containing 5 mg/ml heat-killed Mycobacterium tuberculosis H37Ra (Difco). Pertussis toxin (200 ng, List Biological Laboratories) in PBS was administered i.v. on days 0 and 2. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

Induction and assessment of EAE:

For active EAE induction, age- and sex-matched mice were immunized s.c. with MOG35-55 peptide (300 μg) mixed in CFA (Sigma-Aldrich) containing 5 mg/ml heat-killed Mycobacterium tuberculosis H37Ra (Difco). Pertussis toxin (200 ng, List Biological Laboratories) in PBS was administered i.v. on days 0 and 2. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

https://www.jci.org/articles/view/123801https://www.jci.org/articles/view/1238012019-05-282019-05-2810.1172/JCI12380110.1172/JCI123801Pertussis Toxin from B. pertussis, Lyophilized in BufferPertussis Toxin from B. pertussis, Lyophilized in Bufferjjin4@zju.edu.cnjjin4@zju.edu.cnActivated;Activity;Autoimmune;Biological;Calcium;Cell;Chain;Clinical;Disease;Drug;Exhibit;Experimental;Factor;Function;Heat;Inflammatory;Intracellular;Linked;List;List Biological;Mechanism;Novel;PA;Peptide;Pertussis;Phosphatase;Proliferation;Regulation;Response;Specific;T cell;Target;Terminal;Toxin;Transcription;Translocation;Treatment;The Journal Of Clinical InvestigationActivated;Activity;Autoimmune;Biological;Calcium;Cell;Chain;Clinical;Disease;Drug;Exhibit;Experimental;Factor;Function;Heat;Inflammatory;Intracellular;Linked;List;List Biological;Mechanism;Novel;PA;Peptide;Pertussis;Phosphatase;Proliferation;Regulation;Response;Specific;T cell;Target;Terminal;Toxin;Transcription;Translocation;Treatment;The Journal Of Clinical Investigation180180usp16-mediated-deubiquitination-of-calcineurin-ausp16-mediated-deubiquitination-of-calcineurin-a