title: Virus infection rapidly activates the P58(IPK) pathway, delaying peak kinase activation to enhance viral replication.
abstract: 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.
authors: Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, CSIC, Madrid, Spain. agoodman@med.miami.edu
authors: Alan G
authors: AG
authors: Goodman
authors: Bertrand C W
authors: BC
authors: Tanner
authors: Stewart T
authors: ST
authors: Chang
authors: Mariano
authors: M
authors: Esteban
authors: Michael G
authors: MG
authors: Katze
references: Virus Genes. 1996;12(1):89-94
references: 8879125
references: Virology. 2007 Jun 20;363(1):236-43
references: 17320139
references: J Cell Sci. 2003 May 15;116(Pt 10):1861-2
references: 12692187
references: Mol Cell Biol. 1994 Apr;14(4):2331-42
references: 7511204
references: Mol Cell Biol. 1998 Feb;18(2):859-71
references: 9447982
references: Vaccine. 2005 Apr 27;23(23):2994-3004
references: 15811645
references: Cell. 2002 Feb 22;108(4):545-56
references: 11909525
references: J Virol. 2006 Feb;80(4):2019-33
references: 16439558
references: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10551-5
references: 7937992
references: J Virol. 1999 Mar;73(3):2425-33
references: 9971827
references: FASEB J. 2010 Oct;24(10):4068-77
references: 20484669
references: Science. 2006 Apr 21;312(5772):389-91
references: 16627735
references: J Cell Biol. 1991 Aug;114(3):401-11
references: 1650370
references: J Virol. 2007 Mar;81(5):2221-30
references: 17166899
references: Methods Mol Biol. 2009;487:331-41
references: 19301655
references: Virology. 1993 Apr;193(2):1037-41
references: 8096351
references: PLoS Pathog. 2009 May;5(5):e1000438
references: 19461876
references: EMBO J. 2006 Apr 19;25(8):1730-40
references: 16601681
references: J Virol. 2010 Sep;84(17):8446-59
references: 20554776
references: J Virol. 2000 Jul;74(13):6203-6
references: 10846107
references: J Virol. 1968 Jan;2(1):33-9
references: 5742027
references: Virology. 1995 Dec 1;214(1):222-8
references: 8525619
references: J Biol Chem. 1992 May 5;267(13):9383-90
references: 1577765
references: Diabetes. 2005 Apr;54(4):1074-81
references: 15793246
references: J Virol. 1975 Dec;16(6):1464-75
references: 1202245
references: Virology. 2002 Jul 20;299(1):133-41
references: 12167348
references: Oncogene. 2001 Jan 18;20(3):385-94
references: 11313968
references: Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):97-102
references: 8990167
references: Biochimie. 2007 Jun-Jul;89(6-7):799-811
references: 17451862
references: Virology. 1994 Mar;199(2):491-6
references: 7510087
references: J Virol. 1993 Mar;67(3):1688-92
references: 8094759
references: Antimicrob Agents Chemother. 2007 Aug;51(8):2965-8
references: 17562808
references: J Virol. 2010 Feb;84(4):2027-37
references: 19939913
references: PLoS One. 2011 Jan 26;6(1):e16304
references: 21298103
references: J Virol. 2011 Jan;85(1):550-67
references: 20943971
references: Virol J. 2005 Sep 12;2:81
references: 16156900
references: J Biol Chem. 1992 Jul 15;267(20):14238-43
references: 1378438
references: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4530-5
references: 15767567
references: Mol Cell Biol. 1999 Jul;19(7):4757-65
references: 10373525
references: Cell. 2005 Sep 23;122(6):901-13
references: 16179259