Disease relevance of Eif2ak2

• Activation of PKR by Bunyamwera virus is independent of the viral interferon antagonist NSs [1].
• Surprisingly, cultured embryonic fibroblasts lacking RNase L, PKR, or both proteins were still able to mount a substantial residual antiviral response against encephalomyocarditis virus or vesicular stomatitis virus after IFN-alpha treatments [2].
• These data also suggest that PKR may have a role in preventing progression from splenomegaly to lymphadenopathy in these mice [3].
• Here, we demonstrate that mice lacking PKR are predisposed to lethal intranasal infection by the usually innocuous vesicular stomatitis virus, and also display increased susceptibility to influenza virus infection [4].
• Furthermore, PKR and eIF2alpha Ser-51-dependent autophagy is antagonized by the herpes simplex virus neurovirulence protein, ICP34 [5].

High impact information on Eif2ak2

• Translational resistance of late alphavirus mRNA to eIF2alpha phosphorylation: a strategy to overcome the antiviral effect of protein kinase PKR [6].
• Our findings show the existence of an alternative way to locate the ribosomes on the initiation codon of mRNA that is exploited by a family of viruses to counteract the antiviral effect of PKR [6].
• Our data indicate that in normal cells, PKR primarily prevents virus replication by inhibiting the translation of viral mRNAs through phosphorylation of eIF2alpha, while concomitantly assisting in the production of autocrine IFN and the establishment of an antiviral state [4].
• Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection [4].
• Effects of IFN-gamma on IE1 protein expression were independent of RNaseL and PKR [7].

Chemical compound and disease context of Eif2ak2

• EMCV infection also activates the mitogen-activated protein kinase, cyclic AMP response element binding protein, and nuclear factor kappaB (NF-kappaB) signaling cascades at 15 to 30 min postinfection in PKR+/+ and PKR-/- macrophages [8].
• The murine double-stranded RNA-dependent protein kinase PKR and the murine 2',5'-oligoadenylate synthetase-dependent RNase L are required for IFN-beta-mediated resistance against herpes simplex virus type 1 in primary trigeminal ganglion culture [9].
• In addition, overexpression of the HIV TAR RNA binding protein also inhibited eIF-2 alpha phosphorylation upon A23187 treatment [10].
• Protein synthesis in pseudorabies virus-infected cells: decreased expression of protein kinase PKR, and effects of 2-aminopurine and adenine [11].

Biological context of Eif2ak2

• The mouse PKR gene contains 16 exons and spans about 28 kilobase pairs [12].
• Dissection of anti- and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA responsive protein kinase PKR as a critical mediator of pathogen-induced macrophage apoptosis [13].
• We show that restoration of virulence is specific to ICP34.5 and PKR by using additional host and viral mutants [14].
• Specifically: (i) PKR is activated in infected cells although the effects of the activated enzyme on protein synthesis are negated by the viral gene gamma134.5, which encodes a protein phosphatase 1alpha accessory factor that enables the dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 [15].
• Transfection of the parental M1 cells with the functional wild-type human PKR restricted their proliferation in the absence of interferons [16].

Anatomical context of Eif2ak2

• Moreover, both phosphorylated and unphosphorylated activating transcription factor 2 DNA-binding activities were reduced in PKR-null aortic endothelial cells [17].
• These results implicate PKR for the first time in the growth control of mature T lymphocytes and give insight into the negative regulation of CD8(+) T cell-mediated immune responses [18].
• Isolated lymph node T cells from PKR:(-/-) mice were hyperproliferative during Con A-mediated stimulation [18].
• Expression of IFN-beta resulted in an elevation of the IFN-induced antiviral gene 2',5'-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG) [19].
• Encephalomyocarditis virus induces PKR-independent mitogen-activated protein kinase activation in macrophages [8].

Associations of Eif2ak2 with chemical compounds

• The in vitro synthesized TIK protein migrated as a 65 kDa protein on SDS-PAGE when incubated with ATP, but migrated as a 60 kDa protein when incubated with an inhibitor of PKR, 2-aminopurine [20].
• A dominant-negative mutant PKR cDNA, in which the amino acid lysine at 296 was replaced with arginine and which does not have catalytic activity, was transfected into mouse osteoblastic MC3T3-E1 cells; thereby, we established cells that stably expressed the PKR mutant gene (PKR-K/R) [21].
• PKR is a multifunctional serine/threonine kinase, which is involved in antiviral defense and cell growth control and in the response to various stress signals [22].
• Human gene profiling in response to the active protein kinase, interferon-induced serine/threonine protein kinase (PKR), in infected cells. Involvement of the transcription factor ATF-3 IN PKR-induced apoptosis [23].
• Interaction between RAX and PKR modulates the effect of ethanol on protein synthesis and survival of neurons [24].

Enzymatic interactions of Eif2ak2

• Early studies provided evidence implicating PKR as the kinase that phosphorylates eIF2alpha under conditions of cell stress such as the accumulation of misfolded proteins in the lumen of the endoplasmic reticulum, i.e., the unfolded protein response (UPR) [25].

Regulatory relationships of Eif2ak2

• Thus, PKR acts as a signal transducer for IFN-stimulated genes dependent on the transcription factors IRF-1 and NF-kappaB [26].
• NF-kappaB is activated in wild-type murine embryonic fibroblasts but not in related PKR-null cells [15].
• In this study, we provide evidence that the double-stranded RNA-dependent protein kinase (PKR) is not required for virus-induced expression of inducible nitric oxide synthase (iNOS) or the activation of specific signaling pathways in macrophages [8].

Other interactions of Eif2ak2

• In particular, PKR, RNase L, and Mx are considered to be the principal proteins through which IFNs mount an antiviral state [2].
• The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4 [13].
• Activation of this pathway requires the PKR-dependent degradation of the IkappaBbeta protein [17].
• Mice devoid of functional PKR (Pkr(o/o)) derived by targeted gene disruption exhibit a diminished response to IFN-gamma and poly(rI:rC) (pIC) [26].
• The increase in levels of interferon-inducible proteins p202a and p202b and RNA-dependent protein kinase (PKR) during myoblast differentiation is due to transactivation by MyoD: their tissue distribution in uninfected mice does not depend on interferons [22].

Analytical, diagnostic and therapeutic context of Eif2ak2

• Furthermore, the sensitivity of viruses in cell culture to IFN was independent of PKR and was not determined by NSs [1].
• Immunofluorescence and coimmunoprecipitation studies demonstrated that MDA-7 protein physically interacts with PKR [27].
• The gene encoding the RNA-dependent protein kinase (PKR) was cloned from mouse genomic DNA and characterized by restriction mapping, Southern blot analysis and sequencing [28].
• We have generated a partial cDNA clone, which probably represents the murine p68 kinase, by reverse transcription-polymerase chain reaction (RT-PCR) using sequence information of the human p68 kinase [29].
• We used human cDNA microarrays to identify, in infected cells, genes differentially expressed after PKR expression and analyzed the requirement of catalytic activity of the enzyme [23].

References