Abstract

The positive transcription elongation factor b (P-TEFb) is a critical co-activator 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.

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We uploaded the original data (in the "Source Data" categories ) together with the manuscript onto the eLIFE server.

Article and author information

Author details

  1. Fang Huang

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Trang TT Nguyen

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ignacia Echeverria

    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4717-1467
  4. Rakesh Ramachandran

    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Daniele C. Cary

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hana Paculova

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrej Sali

    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0435-6197
  8. Arthur Weiss

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2414-9024
  9. Boris Matija Peterlin

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Matija.Peterlin@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
  10. Koh Fujinaga

    Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    For correspondence
    koh.fujinaga@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4242-9078

Funding

National Institute of Allergy and Infectious Diseases (R01 AI049104)

  • Fang Huang
  • Daniele C. Cary
  • Hana Paculova
  • Boris Matija Peterlin
  • Koh Fujinaga

National Institute of Allergy and Infectious Diseases (P01 AI091580)

  • Trang TT Nguyen
  • Arthur Weiss

National Institute of Allergy and Infectious Diseases (P50AI150476)

  • Fang Huang
  • Ignacia Echeverria
  • Rakesh Ramachandran
  • Daniele C. Cary
  • Hana Paculova
  • Andrej Sali
  • Boris Matija Peterlin
  • Koh Fujinaga

Howard Hughes Medical Institute

  • Trang TT Nguyen
  • Arthur Weiss

Damon Runyon Cancer Research Foundation

  • Trang TT Nguyen

Nora Eccles Treadwell Foundation

  • Fang Huang
  • Koh Fujinaga

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Eric J Wagner, University of Rochester Medical Center, United States

Version history

  1. Received: March 17, 2021
  2. Preprint posted: May 25, 2021 (view preprint)
  3. Accepted: November 19, 2021
  4. Accepted Manuscript published: November 25, 2021 (version 1)
  5. Version of Record published: December 6, 2021 (version 2)
  6. Version of Record updated: December 21, 2021 (version 3)

Copyright

© 2021, Huang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Fang Huang
  2. Trang TT Nguyen
  3. Ignacia Echeverria
  4. Rakesh Ramachandran
  5. Daniele C. Cary
  6. Hana Paculova
  7. Andrej Sali
  8. Arthur Weiss
  9. Boris Matija Peterlin
  10. Koh Fujinaga
(2021)
Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb
eLife 10:e68473.
https://doi.org/10.7554/eLife.68473

Share this article

https://doi.org/10.7554/eLife.68473

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