The protein kinase regulated by RNA (PKR) and the adenosine deaminase acting on RNA (ADAR1) are interferon-inducible enzymes that play important roles in biologic processes including the antiviral actions of interferons, signal transduction, and apoptosis. PKR catalyzes the RNA-dependent phosphorylation of protein synthesis initiation factor eIF-2α, thereby leading to altered translational patterns in interferon-treated and virus-infected cells. PKR also modulates signal transduction responses, including the induction of interferon. ADAR1 catalyzes the deamination of adenosine (A) to generate inosine (I) in RNAs with double-stranded character. Because I is recognized as G instead of A, A-to-I editing by ADAR1 can lead to genetic recoding and altered RNA structures. The importance of PKR and ADAR1 in innate antiviral immunity is illustrated by a number of viruses that encode either RNA or protein viral gene products that antagonize PKR and ADAR1 enzymatic activity, localization, or stability.
Get full access to this article
View all access options for this article.
References
1.
AbrahamN, StojdlDF, DuncanPI, MethotN, IshiiT, DubeM, VanderhydenBC, AtkinsHL, GrayDA, McBurneyMW, KoromilasAE, BrownEG, SonenbergN, BellJC. 1999. Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J Biol Chem, 274,9:5953–5962.
2.
AthanasiadisA, PlacidoD, MaasS, BrownBAII, LowenhauptK, RichA. 2005. The crystal structure of the Zbeta domain of the RNA-editing enzyme ADAR1 reveals distinct conserved surfaces among Z-domains. J Mol Biol, 351,3:496–507.
3.
BannwarthS, GatignolA. 2005. HIV-1 TAR RNA: the target of molecular interactions between the virus and its host. Curr HIV Res, 3,1:61–71.
4.
BassBL. 2002. RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem, 71:817–846.
5.
BergmannM, Garcia-SastreA, CarneroE, PehambergerH, WolffK, PaleseP, MusterT. 2000. Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication. J Virol, 74,13:6203–6206.
6.
BevilacquaPC, GeorgeCX, SamuelCE, CechTR. 1998. Binding of the protein kinase PKR to RNAs with secondary structure defects: role of the tandem A-G mismatch and noncontiguous helixes. Biochemistry, 37,18:6303–6316.
7.
BlackTL, BarberGN, KatzeMG. 1993. Degradation of the interferon-induced 68,000-M(r) protein kinase by poliovirus requires RNA. J Virol, 67,2:791–800.
8.
BlackTL, SaferB, HovanessianA, KatzeMG. 1989. The cellular 68,000-Mr protein kinase is highly autophosphorylated and activated yet significantly degraded during poliovirus infection: implications for translational regulation. J Virol, 63,5:2244–2251.
9.
BordenEC, SenGC, UzeG, SilvermanRH, RansohoffRM, FosterGR, StarkGR. 2007. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov, 6,12:975–990.
10.
BudtM, NiederstadtL, ValchanovaRS, JonjicS, BruneW. 2009. Specific inhibition of the PKR-mediated antiviral response by the murine cytomegalovirus proteins m142 and m143. J Virol, 83,3:1260–1270.
11.
BuenzEJ, HoweCL. 2006. Picornaviruses and cell death. Trends Microbiol, 14,1:28–36.
12.
BurysekL, PithaPM. 2001. Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. J Virol, 75,5:2345–2352.
CaseyJL. 2006. RNA editing in hepatitis delta virus. Curr Top Microbiol Immunol, 307:67–89.
15.
CassadyKA, GrossM. 2002. The herpes simplex virus type 1 U(S)11 protein interacts with protein kinase R in infected cells and requires a 30-amino-acid sequence adjacent to a kinase substrate domain. J Virol, 76,5:2029–2035.
16.
CattaneoR, SchmidA, EschleD, BaczkoK, ter MeulenV, BilleterMA. 1988. Biased hypermutation and other genetic changes in defective measles viruses in human brain infections. Cell, 55,2:255–265.
17.
ChangHW, WatsonJC, JacobsBL. 1992. The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci USA, 89,11:4825–4829.
18.
ChenCW, TsayYG, WuHL, LeeCH, ChenDS, ChenPJ. 2002. The double-stranded RNA-activated kinase, PKR, can phosphorylate hepatitis D virus small delta antigen at functional serine and threonine residues. J Biol Chem, 277,36:33058–33067.
19.
ChienCY, XuY, XiaoR, AraminiJM, SahasrabudhePV, KrugRM, MontelioneGT. 2004. Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode. Biochemistry, 43,7:1950–1962.
20.
ChildSJ, GeballeAP. 2009. Binding and relocalization of protein kinase R by murine cytomegalovirus. J Virol, 83,4:1790–1799.
21.
ClarkePA, MathewsMB. 1995. Interactions between the double-stranded RNA binding motif and RNA: definition of the binding site for the interferon-induced protein kinase DAI (PKR) on adenovirus VA RNA. RNA, 1,1:7–20.
22.
CoventryVK, ConnGL. 2008. Analysis of adenovirus VA RNAI structure and stability using compensatory base pair modifications. Nucleic Acids Res, 36,5:1645–1653.
23.
DasS, WardSV, TackeRS, SuskeG, SamuelCE. 2006. Activation of the RNA-dependent protein kinase PKR promoter in the absence of interferon is dependent upon Sp proteins. J Biol Chem, 281,6:3244–3253.
24.
DauberB, SchneiderJ, WolffT. 2006. Double-stranded RNA binding of influenza B virus nonstructural NS1 protein inhibits protein kinase R but is not essential to antagonize production of alpha/beta interferon. J Virol, 80,23:11667–11677.
25.
DuboisMF, HovanessianAG. 1990. Modified subcellular localization of interferon-induced p68 kinase during encephalomyocarditis virus infection. Virology, 179,2:591–598.
26.
EckmannCR, NeunteuflA, PfaffstetterL, JantschMF. 2001. The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein. Mol Biol Cell, 12,7:1911–1924.
27.
EldeNC, ChildSJ, GeballeAP, MalikHS. 2009. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature, 457,7228:485–489.
28.
EliaA, LaingKG, SchofieldA, TillerayVJ, ClemensMJ. 1996. Regulation of the double-stranded RNA-dependent protein kinase PKR by RNAs encoded by a repeated sequence in the Epstein-Barr virus genome. Nucleic Acids Res, 24,22:4471–4478.
29.
EssbauerS, BremontM, AhneW. 2001. Comparison of the eIF-2alpha homologous proteins of seven ranaviruses (Iridoviridae)Virus Genes, 23,3:347–359.
30.
FengZ, CervenyM, YanZ, HeB. 2007. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J Virol, 81,1:182–192.
31.
FennerBJ, GohW, KwangJ. 2006. Sequestration and protection of double-stranded RNA by the betanodavirus b2 protein. J Virol, 80,14:6822–6833.
32.
GaineyMD, DillonPJ, ClarkKM, ManuseMJ, ParksGD. 2008. Paramyxovirus-induced shutoff of host and viral protein synthesis: role of the P and V proteins in limiting PKR activation. J Virol, 82,2:828–839.
33.
GalabruJ, KatzeMG, RobertN, HovanessianAG. 1989. The binding of double-stranded RNA and adenovirus VAI RNA to the interferon-induced protein kinase. Eur J Biochem, 178,3:581–589.
34.
GaleMJr, BlakelyCM, KwieciszewskiB, TanSL, DossettM, TangNM, KorthMJ, PolyakSJ, GretchDR, KatzeMG. 1998. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol, 18,9:5208–5218.
35.
GandySZ, LinnstaedtSD, MuralidharS, CashmanKA, RosenthalLJ, CaseyJL. 2007. RNA editing of the human herpesvirus 8 kaposin transcript eliminates its transforming activity and is induced during lytic replication. J Virol, 81,24:13544–13551.
36.
GarciaMA, GilJ, VentosoI, GuerraS, DomingoE, RivasC, EstebanM. 2006. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev, 70,4:1032–1060.
37.
GarciaMA, GuerraS, GilJ, JimenezV, EstebanM. 2002. Antiapoptotic and oncogenic properties of the dsRNA-binding protein of vaccinia virus, E3L. Oncogene, 21,55:8379–8387.
38.
GendronK, CharbonneauJ, DuludeD, HevekerN, FerbeyreG, Brakier-GingrasL. 2008. The presence of the TAR RNA structure alters the programmed-1 ribosomal frameshift efficiency of the human immunodeficiency virus type 1 (HIV-1) by modifying the rate of translation initiation. Nucleic Acids Res, 36,1:30–40.
39.
GeorgeCX, DasS, SamuelCE. 2008. Organization of the mouse RNA-specific adenosine deaminase Adar1 gene 5′-region and demonstration of STAT1-independent, STAT2-dependent transcriptional activation by interferon. Virology, 380,2:338–343.
40.
GeorgeCX, SamuelCE. 1999. Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci USA, 96,8:4621–4626.
41.
GeorgeCX, WagnerMV, SamuelCE. 2005. Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. J Biol Chem, 280,15:15020–15028.
42.
GoodmanAG, SmithJA, BalachandranS, PerwitasariO, ProllSC, ThomasMJ, KorthMJ, BarberGN, SchiffLA, KatzeMG. 2007. The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism. J Virol, 81,5:2221–2230.
43.
GunneryS, GreenSR, MathewsMB. 1992. Tat-responsive region RNA of human immunodeficiency virus type 1 stimulates protein synthesis in vivo and in vitro: relationship between structure and function. Proc Natl Acad Sci USA, 89,23:11557–11561.
44.
HabjanM, PichlmairA, ElliottRM, OverbyAK, GlatterT, GstaigerM, Superti-FurgaG, UngerH, WeberF. 2009. NSs protein of Rift Valley Fever Virus induces the specific degradation of the double-stranded RNA-dependent protein kinase (PKR)J Virol, 83,9:4365–4375.
45.
HakkiM, MarshallEE, De NiroKL, GeballeAP. 2006. Binding and nuclear relocalization of protein kinase R by human cytomegalovirus TRS1. J Virol, 80,23:11817–11826.
46.
HallerO, KochsG, WeberF. 2006. The interferon response circuit: induction and suppression by pathogenic viruses. Virology, 344,1:119–130.
47.
HartnerJC, SchmittwolfC, KispertA, MullerAM, HiguchiM, SeeburgPH. 2004. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem, 279,6:4894–4902.
48.
HartnerJC, WalkleyCR, LuJ, OrkinSH. 2009. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol, 10,1:109–115.
49.
HeB, GrossM, RoizmanB. 1997. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci USA, 94,3:843–848.
50.
HebnerCM, WilsonR, RaderJ, BidderM, LaiminsLA. 2006. Human papillomaviruses target the double-stranded RNA protein kinase pathway. J Gen Virol, 87,Pt 11:3183–3193.
51.
HiguchiM, SingleFN, KohlerM, SommerB, SprengelR, SeeburgPH. 1993. RNA editing of AMPA receptor subunit GluR-B: a base-paired intron–exon structure determines position and efficiency. Cell, 75,7:1361–1370.
52.
IkegamiT, NarayananK, WonS, KamitaniW, PetersCJ, MakinoS. 2009. Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2alpha phosphorylation. PLoS Pathog, 5,2:e1000287.
53.
ImaniF, JacobsBL. 1988. Inhibitory activity for the interferon-induced protein kinase is associated with the reovirus serotype 1 sigma 3 protein. Proc Natl Acad Sci USA, 85,21:7887–7891.
54.
IsaacsA, LindenmannJ. 1957. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci, 147,927:258–267.
55.
JacobsBL, LanglandJO. 1996. When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. Virology, 219,2:339–349.
56.
JayanGC, CaseyJL. 2002. Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression. J Virol, 76,23:12399–12404.
57.
JeffreyIW, KadereitS, MeursEF, MetzgerT, BachmannM, SchwemmleM, HovanessianAG, ClemensMJ. 1995. Nuclear localization of the interferon-inducible protein kinase PKR in human cells and transfected mouse cells. Exp Cell Res, 218,1:17–27.
58.
Jimenez-GarciaLF, GreenSR, MathewsMB, SpectorDL. 1993. Organization of the double-stranded RNA-activated protein kinase DAI and virus-associated VA RNAI in adenovirus-2-infected HeLa cells. J Cell Sci, 106,Pt 1:11–22.
59.
JingX, CervenyM, YangK, HeB. 2004. Replication of herpes simplex virus 1 depends on the gamma 134.5 functions that facilitate virus response to interferon and egress in the different stages of productive infection. J Virol, 78,14:7653–7666.
60.
KatzeMG, DeCoratoD, SaferB, GalabruJ, HovanessianAG. 1987. Adenovirus VAI RNA complexes with the 68 000 Mr protein kinase to regulate its autophosphorylation and activity. EMBO J, 6,3:689–697.
61.
KatzeMG, HeY, GaleMJr. 2002. Viruses and interferon: a fight for supremacy. Nat Rev Immunol, 2,9:675–687.
62.
Kawagishi-KobayashiM, CaoC, LuJ, OzatoK, DeverTE. 2000. Pseudosubstrate inhibition of protein kinase PKR by swine pox virus C8L gene product. Virology, 276,2:424–434.
63.
KazemiS, PapadopoulouS, LiS, SuQ, WangS, YoshimuraA, MatlashewskiG, DeverTE, KoromilasAE. 2004. Control of alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) phosphorylation by the human papillomavirus type 18 E6 oncoprotein: implications for eIF2 alpha-dependent gene expression and cell death. Mol Cell Biol, 24,8:3415–3429.
64.
KesslerM, MathewsMB. 1992. Premature termination and processing of human immunodeficiency virus type 1-promoted transcripts. J Virol, 66,7:4488–4496.
65.
KhooD, PerezC, MohrI. 2002. Characterization of RNA determinants recognized by the arginine- and proline-rich region of Us11, a herpes simplex virus type 1-encoded double-stranded RNA binding protein that prevents PKR activation. J Virol, 76,23:11971–11981.
66.
KimI, LiuCW, PuglisiJD. 2006. Specific recognition of HIV TAR RNA by the dsRNA binding domains (dsRBD1-dsRBD2) of PKR. J Mol Biol, 358,2:430–442.
67.
KitajewskiJ, SchneiderRJ, SaferB, MunemitsuSM, SamuelCE, ThimmappayaB, ShenkT. 1986. Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell, 45,2:195–200.
68.
KuhenKL, VesseyJW, SamuelCE. 1998. Mechanism of interferon action: identification of essential positions within the novel 15-base-pair KCS element required for transcriptional activation of the RNA-dependent protein kinase pkr gene. J Virol, 72,12:9934–9939.
69.
LanglandJO, CameronJM, HeckMC, JancovichJK, JacobsBL. 2006. Inhibition of PKR by RNA and DNA viruses. Virus Res., 119,1:100–110.
70.
LanglandJO, JacobsBL. 2002. The role of the PKR-inhibitory genes, E3L and K3L, in determining vaccinia virus host range. Virology, 299,1:133–141.
71.
LanglandJO, JacobsBL. 2004. Inhibition of PKR by vaccinia virus: role of the N- and C-terminal domains of E3L. Virology, 324,2:419–429.
72.
LanglandJO, PettifordS, JiangB, JacobsBL. 1994. Products of the porcine group C rotavirus NSP3 gene bind specifically to double-stranded RNA and inhibit activation of the interferon-induced protein kinase PKR. J Virol, 68,6:3821–3829.
73.
LeiM, LiuY, SamuelCE. 1998. Adenovirus VAI RNA antagonizes the RNA-editing activity of the ADAR adenosine deaminase. Virology, 245,2:188–196.
74.
LiS, MinJY, KrugRM, SenGC. 2006. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology, 349,1:13–21.
75.
LiuY, EmesonRB, SamuelCE. 1999. Serotonin-2C receptor pre-mRNA editing in rat brain and in vitro by splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1. J Biol Chem, 274,26:18351–18358.
76.
LiuY, GeorgeCX, PattersonJB, SamuelCE. 1997. Functionally distinct double-stranded RNA-binding domains associated with alternative splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase. J Biol Chem, 272,7:4419–4428.
77.
LiuY, LeiM, SamuelCE.2000. Chimeric double-stranded RNA-specific adenosine deaminase ADAR1 proteins reveal functional selectivity of double-stranded RNA-binding domains from ADAR1 and protein kinase PKR. Proc Natl Acad Sci USA, 97,23:12541–12546.
78.
LiuY, SamuelCE. 1996. Mechanism of interferon action: functionally distinct RNA-binding and catalytic domains in the interferon-inducible, double-stranded RNA-specific adenosine deaminase. J Virol, 70,3:1961–1968.
79.
LiuY, SamuelCE. 1999. Editing of glutamate receptor subunit B pre-mRNA by splice-site variants of interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1. J Biol Chem, 274,8:5070–5077.
McCormackSJ, SamuelCE. 1995. Mechanism of interferon action: RNA-binding activity of full-length and R-domain forms of the RNA-dependent protein kinase PKR—determination of KD values for VAI and TAR RNAs. Virology, 206,1:511–519.
86.
McCormackSJ, ThomisDC, SamuelCE. 1992. Mechanism of interferon action: identification of a RNA binding domain within the N-terminal region of the human RNA-dependent P1/eIF-2 alpha protein kinase. Virology, 188,1:47–56.
87.
McKennaSA, KimI, LiuCW, PuglisiJD. 2006. Uncoupling of RNA binding and PKR kinase activation by viral inhibitor RNAs. J Mol Biol, 358,5:1270–1285.
88.
McKennaSA, LindhoutDA, KimI, LiuCW, GelevVM, WagnerG, PuglisiJD. 2007a. Molecular framework for the activation of RNA-dependent protein kinase. J Biol Chem, 282,15:11474–11486.
89.
McKennaSA, LindhoutDA, ShimoikeT, AitkenCE, PuglisiJD. 2007b. Viral dsRNA inhibitors prevent self-association and autophosphorylation of PKR. J Mol Biol, 372,1:103–113.
90.
MelvilleMW, TanSL, WambachM, SongJ, MorimotoRI, KatzeMG. 1999. The cellular inhibitor of the PKR protein kinase, P58(IPK), is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity. J Biol Chem, 274,6:3797–3803.
91.
NaganoY, KojimaY. 1958. [Inhibition of vaccinia infection by a liquid factor in tissues infected by homologous virus.]C R Seances Soc Biol Fil, 152,11:1627–1629.
92.
NieY, ZhaoQ, SuY, YangJH. 2004. Subcellular distribution of ADAR1 isoforms is synergistically determined by three nuclear discrimination signals and a regulatory motif. J Biol Chem, 279,13:13249–13255.
93.
OnukiR, BandoY, SuyamaE, KatayamaT, KawasakiH, BabaT, TohyamaM, TairaK. 2004. An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease. EMBO J, 23,4:959–968.
PattersonJB, SamuelCE. 1995. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol, 15,10:5376–5388.
96.
PetersGA, KhooD, MohrI, SenGC. 2002. Inhibition of PACT-mediated activation of PKR by the herpes simplex virus type 1 Us11 protein. J Virol, 76,21:11054–11064.
97.
PhuphuakratA, KraiwongR, BoonarkartC, LauhakirtiD, LeeTH, AuewarakulP. 2008. Double-stranded RNA adenosine deaminases enhance expression of human immunodeficiency virus type 1 proteins. J Virol, 82,21:10864–10872.
98.
PoppersJ, MulveyM, KhooD, MohrI. 2000. Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein. J Virol, 74,23:11215–11221.
99.
PoppersJ, MulveyM, PerezC, KhooD, MohrI. 2003. Identification of a lytic-cycle Epstein-Barr virus gene product that can regulate PKR activation. J Virol, 77,1:228–236.
100.
PoulsenH, NilssonJ, DamgaardCK, EgebjergJ, KjemsJ. 2001. CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol Cell Biol, 21,22:7862–7871.
101.
RajanP, SwaminathanS, ZhuJ, ColeCN, BarberG, TevethiaMJ, ThimmapayaB. 1995. A novel translational regulation function for the simian virus 40 large-T antigen gene. J Virol, 69,2:785–795.
102.
RandallRE, GoodbournS. 2008. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol, 89,Pt 1:1–47.
103.
ReichPR, ForgetBG, WeissmanSM. 1966. RNA of low molecular weight in KB cells infected with adenovirus type 2. J Mol Biol, 17,2:428–439.
104.
RomanoPR, ZhangF, TanSL, Garcia-BarrioMT, KatzeMG, DeverTE, HinnebuschAG. 1998. Inhibition of double-stranded RNA-dependent protein kinase PKR by vaccinia virus E3: role of complex formation and the E3 N-terminal domain. Mol Cell Biol, 18,12:7304–7316.
105.
RothenburgS, SeoEJ, GibbsJS, DeverTE, DittmarK. 2009. Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nat Struct Mol Biol, 16,1:63–70.
106.
SadlerAJ, WilliamsBR. 2007. Structure and function of the protein kinase R. Curr Top Microbiol Immunol, 316:253–292.
107.
SaelensX, KalaiM, VandenabeeleP. 2001. Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. J Biol Chem, 276,45:41620–41628.
108.
SamuelCE. 1979. Mechanism of interferon action: phosphorylation of protein synthesis initiation factor eIF-2 in interferon-treated human cells by a ribosome-associated kinase processing site specificity similar to hemin-regulated rabbit reticulocyte kinase. Proc Natl Acad Sci USA, 76,2:600–604.
109.
SamuelCE. 1993. The eIF-2 alpha protein kinases, regulators of translation in eukaryotes from yeasts to humans. J Biol Chem, 268,11:7603–7606.
110.
SamuelCE. 2001. Antiviral actions of interferons. Clin Microbiol Rev, 14,4:778–809.
SchneiderRJ, SaferB, MunemitsuSM, SamuelCE, ShenkT. 1985. Adenovirus VAI RNA prevents phosphorylation of the eukaryotic initiation factor 2 alpha subunit subsequent to infection. Proc Natl Acad Sci USA, 82,13:4321–4325.
113.
SenGC. 2001. Viruses and interferons. Annu Rev Microbiol, 55:255–281.
114.
SeoEJ, LiuF, Kawagishi-KobayashiM, UngTL, CaoC, DarAC, SicheriF, DeverTE. 2008. Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L protein. Proc Natl Acad Sci USA, 105,44:16894–16899.
115.
SharpTV, MoonanF, RomashkoA, JoshiB, BarberGN, JagusR. 1998. The vaccinia virus E3L gene product interacts with both the regulatory and the substrate binding regions of PKR: implications for PKR autoregulation. Virology, 250,2:302–315.
116.
SharpTV, SchwemmleM, JeffreyI, LaingK, MellorH, ProudCG, HilseK, ClemensMJ. 1993. Comparative analysis of the regulation of the interferon-inducible protein kinase PKR by Epstein-Barr virus RNAs EBER-1 and EBER-2 and adenovirus VAI RNA. Nucleic Acids Res, 21,19:4483–4490.
117.
ShorsT, KiblerKV, PerkinsKB, Seidler-WulffR, BanaszakMP, JacobsBL. 1997. Complementation of vaccinia virus deleted of the E3L gene by mutants of E3L. Virology, 239,2:269–276.
118.
ShtrichmanR, HeithoffDM, MahanMJ, SamuelCE. 2002. Tissue selectivity of interferon-stimulated gene expression in mice infected with Dam(+) versus Dam(−) Salmonella enterica serovar Typhimurium strains. Infect Immun, 70,10:5579–5588.
119.
SiekierkaJ, MarianoTM, ReichelPA, MathewsMB. 1985. Translational control by adenovirus: lack of virus-associated RNAI during adenovirus infection results in phosphorylation of initiation factor eIF-2 and inhibition of protein synthesis. Proc Natl Acad Sci USA, 82,7:1959–1963.
120.
SpanggordRJ, VuyisichM, BealPA. 2002. Identification of binding sites for both dsRBMs of PKR on kinase-activating and kinase-inhibiting RNA ligands. Biochemistry, 41,14:4511–4520.
121.
StrehblowA, HalleggerM, JantschMF. 2002. Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain. Mol Biol Cell, 13,11:3822–3835.
122.
TakeuchiK, KomatsuT, KitagawaY, SadaK, GotohB. 2008. Sendai virus C protein plays a role in restricting PKR activation by limiting the generation of intracellular double-stranded RNA. J Virol, 82,20:10102–10110.
123.
TanakaH, SamuelCE. 1994. Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. Proc Natl Acad Sci USA, 91,17:7995–7999.
124.
TaylorDR, PuigM, DarnellME, MihalikK, FeinstoneSM. 2005a. New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. J Virol, 79,10:6291–6298.
125.
TaylorDR, ShiST, RomanoPR, BarberGN, LaiMM. 1999. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science, 285,5424:107–110.
126.
TaylorSS, HasteNM, GhoshG. 2005b. PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking. Cell, 122,6:823–825.
127.
ThimmappayaB, WeinbergerC, SchneiderRJ, ShenkT. 1982. Adenovirus VAI RNA is required for efficient translation of viral mRNAs at late times after infection. Cell, 31,3 Pt 2:543–551.
128.
ThomisDC, DoohanJP, SamuelCE. 1992. Mechanism of interferon action: cDNA structure, expression, and regulation of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from human cells. Virology, 188,1:33–46.
129.
TothAM, DevauxP, CattaneoR, SamuelCE. 2009. Protein kinase PKR mediates the apoptosis induction and growth restriction phenotypes of C protein-deficient measles virus. J Virol, 83,2:961–968.
130.
TothAM, ZhangP, DasS, GeorgeCX, SamuelCE. 2006. Interferon action and the double-stranded RNA-dependent enzymes ADAR1 adenosine deaminase and PKR protein kinase. Prog Nucleic Acid Res Mol Biol, 81:369–434.
131.
ValchanovaRS, Picard-MaureauM, BudtM, BruneW. 2006. Murine cytomegalovirus m142 and m143 are both required to block protein kinase R-mediated shutdown of protein synthesis. J Virol, 80,20:10181–10190.
132.
VendeP, TaraporewalaZF, PattonJT. 2002. RNA-binding activity of the rotavirus phosphoprotein NSP5 includes affinity for double-stranded RNA. J Virol, 76,10:5291–5299.
133.
VyasJ, EliaA, ClemensMJ. 2003. Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA. RNA, 9,7:858–870.
WeberF, WagnerV, RasmussenSB, HartmannR, PaludanSR. 2006. Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol, 80,10:5059–5064.
136.
YueZ, ShatkinAJ. 1997. Double-stranded RNA-dependent protein kinase (PKR) is regulated by reovirus structural proteins. Virology, 234,2:364–371.
137.
ZahnRC, SchelpI, UtermohlenO, von LaerD. 2007. A-to-G hypermutation in the genome of lymphocytic choriomeningitis virus. J Virol, 81,2:457–464.
138.
ZhangC, TangJ, XieJ, ZhangH, LiY, ZhangJ, VerpootenD, HeB, CaoY. 2008. A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells. FEBS Lett, 582,2:171–176.
139.
ZhangP, LanglandJO, JacobsBL, SamuelCE. 2009. Protein kinase PKR-dependent activation of mitogen activated protein kinases occurs through mitochondrial adapter IPS-1 and is antagonized by vaccinia virus E3L. J Virol, 83,11:5718–5725.
140.
ZhangP, SamuelCE. 2007. Protein kinase PKR plays a stimulus- and virus-dependent role in apoptotic death and virus multiplication in human cells. J Virol, 81,15:8192–8200.
141.
ZhangP, SamuelCE. 2008. Induction of protein kinase PKR-dependent activation of interferon regulatory factor 3 by vaccinia virus occurs through adapter IPS-1 signaling. J Biol Chem, 283,50:34580–34587.
