Bim nuclear translocation and inactivation by viral interferon regulatory factor

Research output: Contribution to journalArticle

Abstract

Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of the host cell. Human herpesvirus 8 (HHV-8) uses several strategies to block the host's innate antiviral defenses via interference with interferon and apoptotic signaling. Contributors include the four viral interferon regulatory factors (vIRFs 1-4), which function in dominant negative fashion to block cellular IRF activities in addition to targeting IRF signaling-induced proteins such as p53 and inhibiting other inducers of apoptosis such as TGFb receptor-activated Smad transcription factors. Here we identify direct targeting by vIRF-1 of BH3-only pro-apoptotic Bcl-2 family member Bim, a key negative regulator of HHV-8 replication, to effect its inactivation via nuclear translocation. vIRF-1-mediated relocalization of Bim was identified in transfected cells, by both immunofluorescence assay and western analysis of fractionated cell extracts. Also, colocalization of vIRF-1 and Bim was detected in nuclei of lytically infected endothelial cells. In vitro co-precipitation assays using purified vIRF-1 and Bim revealed direct interaction between the proteins, and Bim-binding residues of vIRF-1 were mapped by deletion and point mutagenesis. Generation and experimental utilization of Bim-refractory vIRF-1 variants revealed the importance of vIRF-1:Bim interaction, specifically, in pro-replication and anti-apoptotic activity of vIRF-1. Furthermore, blocking of the interaction with cell-permeable peptide corresponding to the Bim-binding region of vIRF-1 confirmed the relevance of vIRF-1:Bim association to vIRF-1 pro-replication activity. To our knowledge, this is the first report of an IRF protein that interacts with a Bcl-2 family member and of nuclear sequestration of Bim or any other member of the family as a means of inactivation. The data presented reveal a novel mechanism utilized by a virus to control replication-induced apoptosis and suggest that inhibitory targeting of vIRF-1:Bim interaction may provide an effective antiviral strategy.

Original languageEnglish (US)
Article numbere1001031
Pages (from-to)13-14
Number of pages2
JournalPLoS Pathogens
Volume6
Issue number8
DOIs
StatePublished - Aug 2010

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Human Herpesvirus 8
viral interferon regulatory factors
Antiviral Agents
Apoptosis
Viruses
Aptitude
Cell Extracts
Protein Binding
Cell Communication
Mutagenesis
Interferons
Fluorescent Antibody Technique
Proteins
Transcription Factors
Endothelial Cells
Efficiency
Peptides
Infection
In Vitro Techniques

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Bim nuclear translocation and inactivation by viral interferon regulatory factor. / Choi, Young; Nicholas, John.

In: PLoS Pathogens, Vol. 6, No. 8, e1001031, 08.2010, p. 13-14.

Research output: Contribution to journalArticle

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