Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

eLife

Andrej Sali¹  Rakesh Ramachandran²  Ignacia Echeverria²  Hana Paculova³  Boris Matija Peterlin⁴  Koh Fujinaga⁴  Fang Huang⁴  Daniele C Cary⁴  Trang TT Nguyen⁵  Arthur Weiss⁵ 

[1] Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States;Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, and California Institute for Quantitative Biosciences (QBI), San Francisco, United States;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States;Departmentof Cellular Molecular Pharmacology, California Institute for Quantitative Biosciences (QBI), and Department of Bioengineering and Therapeutic Sciences, San Francisco, United States;Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States;Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States;Department of Medicine, San Francisco, United States;Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States;Department of Medicine, San Francisco, United States;The Howard Hughes Medical Institute, San Francisco, United States;

关键词: P-TEFb;    PKC;    PP1;    phosphorylation;    transcription;    anergy;    exhaustion;    Human;    Mouse;   

DOI  :  10.7554/eLife.68473

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The positive transcription elongation factor b (P-TEFb) is a critical coactivator for transcription of most cellular and viral genes, including those of HIV. While P-TEFb is regulated by 7SK snRNA in proliferating cells, P-TEFb is absent due to diminished levels of CycT1 in quiescent and terminally differentiated cells, which has remained unexplored. In these cells, we found that CycT1 not bound to CDK9 is rapidly degraded. Moreover, productive CycT1:CDK9 interactions are increased by PKC-mediated phosphorylation of CycT1 in human cells. Conversely, dephosphorylation of CycT1 by PP1 reverses this process. Thus, PKC inhibitors or removal of PKC by chronic activation results in P-TEFb disassembly and CycT1 degradation. This finding not only recapitulates P-TEFb depletion in resting CD4+ T cells but also in anergic T cells. Importantly, our studies reveal mechanisms of P-TEFb inactivation underlying T cell quiescence, anergy, and exhaustion as well as proviral latency and terminally differentiated cells.

【 授权许可】

CC BY