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J Biol Chem. 2014 Dec 19;289(51):35102-10. doi: 10.1074/jbc.M114.597062. Epub 2014 Oct 28.

HIV-1 Vpu accessory protein induces caspase-mediated cleavage of IRF3 transcription factor.

Author information

1
From the Cell Biology and Metabolism Program, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and.
2
the HIV Drug Resistance Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
3
From the Cell Biology and Metabolism Program, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and bonifacinoj@helix.nih.gov.

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.

KEYWORDS:

Apoptosis; Caspase; Cellular Immune Response; Human Immunodeficiency Virus (HIV); Innate Immunity; Interferon Regulatory Factor 3; Vpu

PMID:
25352594
PMCID:
PMC4271200
DOI:
10.1074/jbc.M114.597062
[Indexed for MEDLINE]
Free PMC Article

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