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

Authors
  • Huang, Fang1, 2
  • Nguyen, Trang Tt1, 2, 3
  • Echeverria, Ignacia4, 5
  • Ramachandran, Rakesh4, 5
  • Cary, Daniele C1, 2
  • Paculova, Hana1
  • Sali, Andrej4, 6
  • Weiss, Arthur1, 2, 3
  • Peterlin, Boris Matija1, 2
  • Fujinaga, Koh1, 2
  • 1 Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States. , (United States)
  • 2 Department of Medicine, San Francisco, United States. , (United States)
  • 3 The Howard Hughes Medical Institute, San Francisco, United States. , (United States)
  • 4 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States. , (United States)
  • 5 Departmentof Cellular Molecular Pharmacology, California Institute for Quantitative Biosciences (QBI), and Department of Bioengineering and Therapeutic Sciences, San Francisco, United States. , (United States)
  • 6 Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, and California Institute for Quantitative Biosciences (QBI), San Francisco, United States. , (United States)
Type
Published Article
Journal
eLife
Publisher
"eLife Sciences Organisation, Ltd."
Publication Date
Nov 25, 2021
Volume
10
Identifiers
DOI: 10.7554/eLife.68473
PMID: 34821217
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2021, Huang et al.

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