title: Inhibition of β-TrcP-dependent ubiquitination of p53 by HIV-1 Vpu promotes p53-mediated apoptosis in human T cells.
abstract: HIV-1 viral protein U (Vpu) is involved in ubiquitination and degradation of BM stromal cell Ag 2 and surface receptor CD4 through their recruitment to SCF(β-TrcP) (Skp1/Cul1/F-box) ubiquitin ligase (SCF) complex. Here, we show that specific interaction of wild-type Vpu protein with SCF complex leads to inhibition of ubiquitination and proteasomal degradation of p53 protein in a β-TrcP-dependent manner. Successful interaction of SCF(β-TrcP) complex with β-TrcP binding motif (DS(52)GNES(56)) present in Vpu is essential because mutant Vpu possessing specific alanine substitutions (DA(52)GNEA(56)) in the β-TrcP binding motif not only failed to stabilize p53 protein but was also unable to inhibit ubiquitination of p53 protein. Furthermore, Vpu competes efficiently with the interaction of p53 protein with the β-TrcP subunit of the SCF complex and inhibits subsequent ubiquitination of p53 proteins in a dose-dependent manner. We also observed potent apoptotic activity in a p53 null cell line (H-1299) that was cotransfected with p53 and Vpu-expressing plasmids. Furthermore, MOLT-3 (human T-lymphoblast) cells when infected with vesicular stomatitis virus glycoprotein-pseudotypic HIV-1 possessing wild-type vpu gene exhibited maximum activation of p53/Bax proteins and p53-mediated cell death. These findings establish a novel function of Vpu in modulating the stability of p53 protein that correlates positively with apoptosis during late stages of HIV-1 infection.
authors.affiliation: Laboratory of Virology, National Institute of Immunology, New Delhi, India.
authors.forename: Sachin
authors.initials: S
authors.lastname: Verma
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Sakshi
authors.initials: S
authors.lastname: Arora
authors.forename: Akhil C
authors.initials: AC
authors.lastname: Banerjea
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology; D055550:Protein Stability / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology*; D054875:Ubiquitination / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D044844:beta-Transducin Repeat-Containing Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D054298:Human Immunodeficiency Virus Proteins; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins