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

Sang Yoon Park; Abdul A Waheed; Zai-Rong Zhang; Eric O Freed; Juan S Bonifacino

doi:10.1074/jbc.M114.597062

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

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

Authors

Sang Yoon Park¹, Abdul A Waheed², Zai-Rong Zhang¹, Eric O Freed², Juan S Bonifacino³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Apoptosis
Caspases / metabolism*
HEK293 Cells
HIV-1 / genetics
HIV-1 / metabolism*
HIV-1 / physiology
Host-Pathogen Interactions
Human Immunodeficiency Virus Proteins / genetics
Human Immunodeficiency Virus Proteins / metabolism*
Humans
Immunoblotting
Interferon Regulatory Factor-3 / genetics
Interferon Regulatory Factor-3 / metabolism*
Jurkat Cells
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mutation
Poly(ADP-ribose) Polymerases / metabolism
Proteolysis
Transfection
Viral Envelope Proteins / genetics
Viral Envelope Proteins / metabolism
Viral Regulatory and Accessory Proteins / genetics
Viral Regulatory and Accessory Proteins / metabolism*
vif Gene Products, Human Immunodeficiency Virus / genetics
vif Gene Products, Human Immunodeficiency Virus / metabolism
vpr Gene Products, Human Immunodeficiency Virus / genetics
vpr Gene Products, Human Immunodeficiency Virus / metabolism

Substances

G protein, vesicular stomatitis virus
Human Immunodeficiency Virus Proteins
IRF3 protein, human
Interferon Regulatory Factor-3
Membrane Glycoproteins
Viral Envelope Proteins
Viral Regulatory and Accessory Proteins
vif Gene Products, Human Immunodeficiency Virus
vif protein, Human immunodeficiency virus 1
vpr Gene Products, Human Immunodeficiency Virus
vpr protein, Human immunodeficiency virus 1
vpu protein, Human immunodeficiency virus 1
Poly(ADP-ribose) Polymerases
Caspases

Abstract

Publication types

MeSH terms

Substances

Grants and funding