Programmed cell death or apoptosis is a built-in, signal-induced process by which a cell self-destructs. It is a mechanism that provides control of cell numbers, and is therefore critical for normal development and tissue homeostasis. In humans, aberrant programmed cell death is associated with tumorigenesis, neurodegenerative diseases, immunodeficiency, and viral pathogenesis. Although the apoptotic pathway is highly conserved between diverse organisms and involves central death regulators, the cellular mechanisms involved in execution and regulation of apoptosis are largely unknown. Animal viruses that induce apoptosis can block cell death by the expression of novel apoptotic suppressors. The mechanisms for viral intervention of host apoptosis have therefore provided key insight into the cell death program. It is the long term objective of this proposal to define the molecular mechanisms by which apoptosis is regulated through the study of the baculovirus-encoded apoptotic regulators, p35 and iap. Our approach focuses on the use of baculovirus-infected insect cells as a powerful, yet convenient system for molecular analysis of the induction and suppression of apoptosis. In an integrated set of experiments that build on recent advances in programmed cell death, we use biochemical, genetic, and cell biology approaches to determine the molecular mechanism of P35 and vIAP anti- apoptotic activity. An extensive collection of loss-of-function p35 mutations will be used to characterize the molecular interaction between P35 and the CED-3/ICE-related death proteases, for which P35 is a potent inhibitor. By focusing on the invertebrate CED-3/ICE-like protease(s) induced by baculovirus infection, we also investigate the mechanisms involved in activation and inhibition of these critical cell death enzymes. In genetic studies, we use novel p35- and iap-expressing baculovirus recombinants, as well as stably transfected insect cell lines, to definitively place the anti-apoptotic activity of P35 and vIAP into the conserved death pathway. Lastly, we use p35 and iap as tools to define the mechanisms by which large DNA viruses trigger apoptosis in their host cell and contribute to pathogenesis. Collectively, these studies are expected to yield important insight into the mechanisms by which programmed cell death is regulated and thereby facilitate the long term design of novel therapeutic strategies for treatment of apoptosis- linked human disorders.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Virology Study Section (VR)
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University of Wisconsin Madison
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Byers, Nathaniel M; Vandergaast, Rianna L; Friesen, Paul D (2016) Baculovirus Inhibitor-of-Apoptosis Op-IAP3 Blocks Apoptosis by Interaction with and Stabilization of a Host Insect Cellular IAP. J Virol 90:533-44
Vandergaast, Rianna; Mitchell, Jonathan K; Byers, Nathaniel M et al. (2015) Insect inhibitor-of-apoptosis (IAP) proteins are negatively regulated by signal-induced N-terminal degrons absent within viral IAP proteins. J Virol 89:4481-93
Mitchell, Jonathan K; Byers, Nathaniel M; Friesen, Paul D (2013) Baculovirus F-box protein LEF-7 modifies the host DNA damage response to enhance virus multiplication. J Virol 87:12592-9
Taggart, David J; Mitchell, Jonathan K; Friesen, Paul D (2012) A conserved N-terminal domain mediates required DNA replication activities and phosphorylation of the transcriptional activator IE1 of Autographa californica multicapsid nucleopolyhedrovirus. J Virol 86:6575-85
Mitchell, Jonathan K; Friesen, Paul D (2012) Baculoviruses modulate a proapoptotic DNA damage response to promote virus multiplication. J Virol 86:13542-53
Vandergaast, Rianna; Schultz, Kimberly L W; Cerio, Rebecca J et al. (2011) Active depletion of host cell inhibitor-of-apoptosis proteins triggers apoptosis upon baculovirus DNA replication. J Virol 85:8348-58
Cerio, Rebecca J; Vandergaast, Rianna; Friesen, Paul D (2010) Host insect inhibitor-of-apoptosis SfIAP functionally replaces baculovirus IAP but is differentially regulated by Its N-terminal leader. J Virol 84:11448-60
Schultz, Kimberly L W; Friesen, Paul D (2009) Baculovirus DNA replication-specific expression factors trigger apoptosis and shutoff of host protein synthesis during infection. J Virol 83:11123-32
Schultz, Kimberly L W; Wetter, Justin A; Fiore, Diccon C et al. (2009) Transactivator IE1 is required for baculovirus early replication events that trigger apoptosis in permissive and nonpermissive cells. J Virol 83:262-72
Guy, Michael P; Friesen, Paul D (2008) Reactive-site cleavage residues confer target specificity to baculovirus P49, a dimeric member of the P35 family of caspase inhibitors. J Virol 82:7504-14

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