title: HIV-1 Vpu accessory protein induces caspase-mediated cleavage of IRF3 transcription factor.
abstract: Vpu is an accessory protein encoded by HIV-1 that interferes with multiple host-cell functions. Herein we report that expression of Vpu by transfection into 293T cells causes partial proteolytic cleavage of interferon regulatory factor 3 (IRF3), a key transcription factor in the innate anti-viral response. Vpu-induced IRF3 cleavage is mediated by caspases and occurs mainly at Asp-121. Cleavage produces a C-terminal fragment of ∼37 kDa that comprises the IRF dimerization and transactivation domains but lacks the DNA-binding domain. A similar cleavage is observed upon infection of the Jurkat T-cell line with vesicular stomatitis virus G glycoprotein (VSV-G)-pseudotyped HIV-1. Two other HIV-1 accessory proteins, Vif and Vpr, also contribute to the induction of IRF3 cleavage in both the transfection and the infection systems. The C-terminal IRF3 fragment interferes with the transcriptional activity of full-length IRF3. Cleavage of IRF3 under all of these conditions correlates with cleavage of poly(ADP-ribose) polymerase, an indicator of apoptosis. We conclude that Vpu contributes to the attenuation of the anti-viral response by partial inactivation of IRF3 while host cells undergo apoptosis.
authors.affiliation: From the Cell Biology and Metabolism Program, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Park
authors.affiliation: the HIV Drug Resistance Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Abdul A
authors.initials: AA
authors.lastname: Waheed
authors.affiliation: From the Cell Biology and Metabolism Program, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Zai-Rong
authors.initials: ZR
authors.lastname: Zhang
authors.affiliation: the HIV Drug Resistance Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
authors.affiliation: From the Cell Biology and Metabolism Program, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and bonifacinoj@helix.nih.gov.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059748:Proteolysis; D014162:Transfection; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D020169:Caspases; D054298:Human Immunodeficiency Virus Proteins; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins; D011065:Poly(ADP-ribose) Polymerases; D014759:Viral Envelope Proteins; D054334:Viral Regulatory and Accessory Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; C028391:G protein, vesicular stomatitis virus; C494232:IRF3 protein, human; C514847:vif protein, Human immunodeficiency virus 1; C514912:vpr protein, Human immunodeficiency virus 1; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
keywords: Apoptosis; Caspase; Cellular Immune Response; Human Immunodeficiency Virus (HIV); Innate Immunity; Interferon Regulatory Factor 3; Vpu