Document Detail

Active depletion of host cell inhibitor-of-apoptosis proteins triggers apoptosis upon baculovirus DNA replication.
MedLine Citation:
PMID:  21653668     Owner:  NLM     Status:  MEDLINE    
Apoptosis is an important antivirus defense by virtue of its impact on virus multiplication and pathogenesis. To define molecular mechanisms by which viruses are detected and the apoptotic response is initiated, we examined the antiviral role of host inhibitor-of-apoptosis (IAP) proteins in insect cells. We report here that the principal IAPs, DIAP1 and SfIAP, of the model insects Drosophila melanogaster and Spodoptera frugiperda, respectively, are rapidly depleted and thereby inactivated upon infection with the apoptosis-inducing baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV). Virus-induced loss of these host IAPs triggered caspase activation and apoptotic death. Elevation of IAP levels by ectopic expression repressed caspase activation. Loss of host IAP in both species was triggered by AcMNPV DNA replication. By using selected inhibitors, we found that virus-induced IAP depletion was mediated in part by the proteasome but not by caspase cleavage. Consistent with this conclusion, mutagenic disruption of the SfIAP RING motif, which acts as an E3 ubiquitin ligase, stabilized SfIAP during infection. Importantly, SfIAP was also stabilized upon the removal of its 99-residue N-terminal leader, which serves as a critical determinant of IAP turnover. These data indicated that a host pathway initiated by virus DNA replication and acting through instability motifs embedded within IAP triggers IAP depletion and thereby causes apoptosis. Taken together, the results of our study suggest that host modulation of cellular IAP levels is a conserved mechanism by which insects mount an apoptotic antiviral response. Thus, host IAPs may function as critical sentinels of virus invasion in insects.
Rianna Vandergaast; Kimberly L W Schultz; Rebecca J Cerio; Paul D Friesen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-08
Journal Detail:
Title:  Journal of virology     Volume:  85     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-21     Completed Date:  2011-10-04     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8348-58     Citation Subset:  IM    
Institute for Molecular Virology, Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1596, USA.
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MeSH Terms
Baculoviridae / genetics,  pathogenicity,  physiology*
Caspases / biosynthesis,  metabolism
Cell Line
DNA Replication*
Drosophila Proteins / biosynthesis,  genetics,  metabolism*
Drosophila melanogaster / virology
Inhibitor of Apoptosis Proteins / biosynthesis,  genetics,  metabolism*
Insect Proteins / biosynthesis,  genetics,  metabolism*
RNA Interference
RNA, Small Interfering
Spodoptera / virology
Virus Replication*
Grant Support
Reg. No./Substance:
0/Drosophila Proteins; 0/Inhibitor of Apoptosis Proteins; 0/Insect Proteins; 0/RNA, Small Interfering; 0/thread protein, Drosophila; EC 3.4.22.-/Caspases

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