title: USP7 deubiquitinase controls HIV-1 production by stabilizing Tat protein.
abstract: Deubiquitinases (DUBs) are key regulators of complex cellular processes. HIV-1 Tat is synthesized early after infection and is mainly responsible for enhancing viral production. Here, we report that one of the DUBs, USP7, stabilized the HIV-1 Tat protein through its deubiquitination. Treatment with either a general DUB inhibitor (PR-619) or USP7-specific inhibitor (P5091) resulted in Tat protein degradation. The USP7-specific inhibitor reduced virus production in a latently infected T-lymphocytic cell line J1.1, which produces large amounts of HIV-1 upon stimulation. A potent increase in Tat-mediated HIV-1 production was observed with USP7 in a dose-dependent manner. As expected, deletion of the USP7 gene using the CRISPR-Cas9 method reduced the Tat protein and supported less virus production. Interestingly, the levels of endogenous USP7 increased after HIV-1 infection in human T-cells (MOLT-3) and in mammalian cells transfected with HIV-1 proviral DNA. Thus, HIV-1 Tat is stabilized by the host cell deubiquitinase USP7, leading to enhanced viral production, and HIV-1 in turn up-regulates the USP7 protein level.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Rameez
authors.initials: R
authors.lastname: Raja
authors.affiliation: Laboratory of Virology, National Institute of Immunology, New Delhi, India.
authors.forename: Sabihur Rahman
authors.initials: SR
authors.lastname: Farooqui
authors.affiliation: Laboratory of Virology, National Institute of Immunology, New Delhi, India.
authors.forename: Shaista
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Laboratory of Virology, National Institute of Immunology, New Delhi, India akhil@nii.res.in akhil@nii.ac.in.
authors.forename: Akhil C
authors.initials: AC
authors.lastname: Banerjea
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology; D064113:CRISPR-Cas Systems; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter / Q000187:drug effects; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D055550:Protein Stability / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D013861:Thiocyanates / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C570894:2,6-diaminopyridine-3,5-bis(thiocyanate); D000631:Aminopyridines; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; C576408:P5091; D011993:Recombinant Fusion Proteins; D013861:Thiocyanates; D013876:Thiophenes; D054322:tat Gene Products, Human Immunodeficiency Virus; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
keywords: HIV-1; deubiquitination; protein degradation; transactivation