title: HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation.
abstract: In addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. We previously demonstrated that Tat modulated both viral and host transcriptional machinery by interacting with the cellular transcription factor interferon regulatory factor 1 (IRF-1). In the present study, we investigated the mechanistic basis and functional significance of Tat-IRF-1 interaction and demonstrate that Tat dramatically decreased IRF-1 protein stability. To accomplish this, Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection. These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses.
  
  
  
  Current therapies have dramatically reduced morbidity and mortality associated with HIV infection and have converted infection from a fatal pathology to a chronic disease that is manageable via antiretroviral therapy. Nevertheless, HIV-1 infection remains a challenge, and the identification of useful cellular targets for therapeutic intervention remains a major goal. The cellular transcription factor IRF-1 impacts various physiological functions, including the immune response to viral infection. In this study, we have identified a unique mechanism by which HIV-1 evades IRF-1-mediated host immune responses and show that the viral protein Tat accelerates IRF-1 proteasome-mediated degradation and inactivates IRF-1 function. Restoration of IRF-1 functionality may thus be regarded as a potential strategy to reinstate both a direct antiviral response and a more broadly acting immune regulatory circuit.
authors: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors: Anna Lisa
authors: AL
authors: Remoli
authors: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors: Giulia
authors: G
authors: Marsili
authors: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors: Edvige
authors: E
authors: Perrotti
authors: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors: Chiara
authors: C
authors: Acchioni
authors: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors: Marco
authors: M
authors: Sgarbanti
authors: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
authors: Alessandra
authors: A
authors: Borsetti
authors: Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
authors: John
authors: J
authors: Hiscott
authors: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy angela.battistini@iss.it.
authors: Angela
authors: A
authors: Battistini
mesh_terms: D002460:Cell Line; D015497:HIV-1 / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D054875:Ubiquitination; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D054322:tat Gene Products, Human Immunodeficiency Virus; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2