The HIV-1 Tat protein recruits a ubiquitin ligase to reorganize the 7SK snRNP for transcriptional activation

ELife
Tyler B FaustAlan D Frankel

Abstract

The HIV-1 Tat protein hijacks P-TEFb kinase to activate paused RNA polymerase II (RNAP II) at the viral promoter. Tat binds additional host factors, but it is unclear how they regulate RNAP II elongation. Here, we identify the cytoplasmic ubiquitin ligase UBE2O as critical for Tat transcriptional activity. Tat hijacks UBE2O to ubiquitinate the P-TEFb kinase inhibitor HEXIM1 of the 7SK snRNP, a fraction of which also resides in the cytoplasm bound to P-TEFb. HEXIM1 ubiquitination sequesters it in the cytoplasm and releases P-TEFb from the inhibitory 7SK complex. Free P-TEFb then becomes enriched in chromatin, a process that is also stimulated by treating cells with a CDK9 inhibitor. Finally, we demonstrate that UBE2O is critical for P-TEFb recruitment to the HIV-1 promoter. Together, the data support a unique model of elongation control where non-degradative ubiquitination of nuclear and cytoplasmic 7SK snRNP pools increases P-TEFb levels for transcriptional activation.

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Citations

Sep 20, 2018·Transcription·Curtis W Bacon, Iván D'Orso
May 28, 2019·Genes & Development·Leighton Core, Karen Adelman
Mar 20, 2019·The Journal of Biological Chemistry·Amjad AliAkhil C Banerjea
Jun 12, 2020·International Journal of Molecular Sciences·Haidong Gu, Behdokht Jan Fada
May 24, 2020·Viruses·Ashutosh ShuklaIván D'Orso
Jun 24, 2020·Nature Chemical Biology·Pabitra K Parua, Robert P Fisher
Dec 9, 2020·Viruses·Antoine DutilleulCarine Van Lint
May 28, 2021·Frontiers in Oncology·Abel Tesfaye AnshaboHugo Albrecht
Jun 20, 2021·Cellular and Molecular Life Sciences : CMLS·Sylvain Egloff
Jul 10, 2021·Biochimie·Amjad AliAkhil Chandra Banerjea

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Methods Mentioned

BETA
ubiquitination
transfection
transfections
Gel filtration
Tandem affinity purification
pull-down
pull-downs
RNA-IP
immunoprecipitation
ChIP

Software Mentioned

PolyJet
MaxQuant

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