Document Detail


Baculoviruses modulate a proapoptotic DNA damage response to promote virus multiplication.
MedLine Citation:
PMID:  23035220     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) initiates apoptosis in diverse insects through events triggered by virus DNA (vDNA) replication. To define the proapoptotic pathway and its role in antivirus defense, we investigated the link between the host's DNA damage response (DDR) and apoptosis. We report here that AcMNPV elicits a DDR in the model insect Drosophila melanogaster. Replication of vDNA activated DDR kinases, as evidenced by ATM-driven phosphorylation of the Drosophila histone H2AX homolog (H2Av), a critical regulator of the DDR. Ablation or inhibition of ATM repressed H2Av phosphorylation and blocked virus-induced apoptosis. The DDR kinase inhibitors caffeine and KU55933 also prevented virus-induced apoptosis in cells derived from the permissive AcMNPV host, Spodoptera frugiperda. This block occurred at a step upstream of virus-mediated depletion of the cellular inhibitor-of-apoptosis protein, an event that initiates apoptosis in Spodoptera and Drosophila. Thus, the DDR is a conserved, proapoptotic response to baculovirus infection. DDR inhibition also repressed vDNA replication and reduced virus yields 100,000-fold, demonstrating that the DDR contributes to virus production, despite its recognized antivirus role. In contrast to virus-induced phosphorylation of Drosophila H2Av, AcMNPV blocked phosphorylation of the Spodoptera H2AX homolog (SfH2AX). Remarkably, AcMNPV also suppressed SfH2AX phosphorylation following pharmacologically induced DNA damage. These findings indicate that AcMNPV alters canonical DDR signaling in permissive cells. We conclude that AcMNPV triggers a proapoptotic DDR that is subsequently modified, presumably to stimulate vDNA replication. Thus, manipulation of the DDR to facilitate multiplication is an evolutionarily conserved strategy among DNA viruses of insects and mammals.
Authors:
Jonathan K Mitchell; Paul D Friesen
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-03
Journal Detail:
Title:  Journal of virology     Volume:  86     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-20     Completed Date:  2013-01-28     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13542-53     Citation Subset:  IM    
Affiliation:
Institute for Molecular Virology, Department of Biochemistry, Graduate School and College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Apoptosis / physiology*
Base Sequence
DNA Damage*
DNA Primers
Drosophila melanogaster
Histones / chemistry,  metabolism
Molecular Sequence Data
Nucleopolyhedrovirus / physiology*
Phosphorylation
Polymerase Chain Reaction
Sequence Homology, Amino Acid
Sf9 Cells
Virus Replication / physiology*
Grant Support
ID/Acronym/Agency:
AI25557/AI/NIAID NIH HHS; AI40482/AI/NIAID NIH HHS; T32 GM07125/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Histones
Comments/Corrections

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