VIRUS INFECTION RAPIDLY ACTIVATES THE P58IPK PATHWAY, DELAYING PEAK KINASE ACTIVATION TO ENHANCE VIRAL REPLICATION

ALAN G GOODMAN; BERTRAND C. W TANNER; STEWART T CHANG; MARIANO ESTEBAN; MICHAEL G KATZE

doi:10.1016/j.virol.2011.04.020

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VIRUS INFECTION RAPIDLY ACTIVATES THE P58IPK PATHWAY, DELAYING PEAK KINASE ACTIVATION TO ENHANCE VIRAL REPLICATION

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VIRUS INFECTION RAPIDLY ACTIVATES THE P58IPK PATHWAY, DELAYING PEAK KINASE ACTIVATION TO ENHANCE VIRAL REPLICATION

ALAN G GOODMAN, BERTRAND C. W TANNER, STEWART T CHANG, MARIANO ESTEBAN and MICHAEL G KATZE

Virology (New York, N.Y.), Vol.417(1), pp.27-36

08/15/2011

DOI: https://doi.org/10.1016/j.virol.2011.04.020

Handle:

https://hdl.handle.net/2376/104955

PMCID: PMC3152592

PMID: 21612809

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Abstract

mathematical model

influenza virus

vaccinia virus

P58IPK and Dnajc3

sensitivity analysis

Previously we showed that the cellular protein P58 IPK contributes to viral protein synthesis by decreasing the activity of the anti-viral protein, PKR. Here, we constructed a mathematical model to examine the P58 IPK pathway and investigated temporal behavior of this biological system. We find that influenza virus infection results in the rapid activation of P58 IPK which delays and reduces maximal PKR and eIF2α phosphorylation, leading to increased viral protein levels. We confirmed that the model could accurately predict viral and host protein levels at extended time points by testing it against experimental data. Sensitivity analysis of relative reaction rates describing P58 IPK activity and the downstream proteins through which it functions helped identify processes that may be the most beneficial targets to thwart virus replication. Together, our study demonstrates how computational modeling can guide experimental design to further understand a specific metabolic signaling pathway during viral infection in a mammalian system.

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Title: VIRUS INFECTION RAPIDLY ACTIVATES THE P58IPK PATHWAY, DELAYING PEAK KINASE ACTIVATION TO ENHANCE VIRAL REPLICATION
Creators: ALAN G GOODMAN - Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, CSIC, Madrid, Spain
BERTRAND C. W TANNER - Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405
STEWART T CHANG - Department of Microbiology, University of Washington, Seattle, WA 98195
MARIANO ESTEBAN - Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, CSIC, Madrid, Spain
MICHAEL G KATZE - Department of Microbiology, University of Washington, Seattle, WA 98195
Publication Details: Virology (New York, N.Y.), Vol.417(1), pp.27-36
Academic Unit: Molecular Biosciences, School of
Grant note: R01 AI022646-24 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
Identifiers: 99900546827101842
Language: English
Resource Type: Journal article