Affinage

EIF2AK2

Interferon-induced, double-stranded RNA-activated protein kinase · UniProt P19525

Length
551 aa
Mass
62.1 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2AK2/PKR is a dsRNA-activated serine/threonine kinase that couples detection of double-stranded RNA to global translational control and innate immune signaling (PMID:10557102). Activation is conformational and dimerization-dependent: an inhibitory intramolecular contact between a kinase-domain motif and the dsRNA-binding domain keeps PKR latent, and dsRNA binding relieves this autoinhibition by recruiting two monomers onto a single duplex (minimally ~30 bp) to drive back-to-back kinase-domain dimerization (PMID:18599071, PMID:16785445, PMID:16179248). Dimerization triggers cis-autophosphorylation at Thr-446 in the activation loop, allosterically coupling the dimerization and substrate interfaces so that activated PKR phosphorylates eIF2α to block translation initiation (PMID:16179248, PMID:24338483). The duplex length and structure of the activating RNA dictate productive dimer geometry, and PKR can also be activated through its kinase domain by non-RNA ligands such as heparin, indicating that dimerization—not nucleic-acid binding per se—is the activating event (PMID:19445956, PMID:21978664, PMID:26488609). Beyond viral dsRNA, PKR senses endogenous ligands including inverted-Alu repeat RNAs exposed during mitosis and mitochondrial dsRNA released upon loss of mitochondrial RNA turnover, linking it to cell-cycle translational suppression and to renal tubular injury (PMID:24939934, PMID:30174290, PMID:36869030). PKR also functions as a substrate kinase beyond eIF2α, directly phosphorylating α-synuclein on Ser-129 (PMID:29501855). Functionally, PKR is an apoptotic and inflammatory effector: it mediates macrophage death downstream of TLR4 via IRF3 (PMID:15029200), drives ribotoxic-stress MAPK signaling (JNK/p38/ERK) and apoptosis (PMID:12773753), and acts as a temporal switch using kinase-independent NF-κB survival signaling versus kinase-dependent eIF2α-mediated death (PMID:14749731). Its activity is tightly set by competing regulators—PACT/PRKRA and APOBEC3B-PABPC1 promote activation, while STAT3, ADAR1, and endogenous circRNAs inhibit it—and viral antagonists (HCV E2 and NS5A, vaccinia K3L pseudosubstrate, EBER/VA-I RNAs) suppress PKR to evade the antiviral response (PMID:10390359, PMID:16785445, PMID:16580685, PMID:29429924, PMID:23221979, PMID:39146181, PMID:31031002, PMID:11040133, PMID:11904369, PMID:36781883). Spatially, dsRNA induces cytosolic PKR condensates that organize and buffer downstream eIF2α phosphorylation (PMID:35939694, PMID:35522180). Bidirectional EIF2AK2 missense variants cause neurological disease: gain-of-function alleles with enhanced eIF2α phosphorylation underlie dystonia, while loss-of-function alleles cause a neurodevelopmental syndrome (PMID:33236446, PMID:32197074).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    Establishing the human and mouse chromosomal location of EIF2AK2 provided the genomic anchor for subsequent functional and genetic study.

    Evidence Somatic cell hybrid panels and FISH mapping to human 2p21-p22 and mouse chromosome 17 E2

    PMID:7686883 PMID:7686884

    Open questions at the time
    • Mapping alone established no function
    • No gene structure or regulatory elements defined
  2. 1999 High

    Defining the core enzymatic logic—dsRNA binding triggers autophosphorylation, which enables eIF2α phosphorylation and translational shutdown—answered what PKR does at the molecular level.

    Evidence In vitro kinase assays and dsRNA-activated cell-based assays

    PMID:10557102

    Open questions at the time
    • Structural basis of dsRNA-driven activation not resolved
    • Stoichiometry of activation undefined at this stage
  3. 2005 High

    Crystal structures of the PKR–eIF2α complex revealed back-to-back parallel dimerization as the activation mechanism and showed how substrate docks, settling how activation and substrate recognition are coupled.

    Evidence X-ray crystallography with mutagenesis validation

    PMID:16179248

    Open questions at the time
    • Did not show how dsRNA length controls dimer geometry
    • Did not resolve the autoinhibited latent state
  4. 2008 High

    Biophysical reconstitution established that dimerization is the activating event—a minimal ~30 bp duplex binds two monomers—distinguishing RNA binding from kinase activation.

    Evidence Analytical ultracentrifugation and length-defined autophosphorylation assays; complemented by RNA-dimerization and pseudosubstrate residue studies

    PMID:18599071 PMID:18971339 PMID:19043413 PMID:19445956

    Open questions at the time
    • In-cell relevance of minimal duplex thresholds untested at the time
    • Did not address non-RNA activators
  5. 2006 High

    Identifying an intramolecular autoinhibitory contact between the kinase domain and dsRNA-binding domain explained how PKR is held latent and how PACT and dsRNA relieve inhibition.

    Evidence NMR mapping, point mutagenesis yielding constitutively active PKR, genetic complementation; inhibitory RNAs (EBER/VA-I) shown to bind but not activate

    PMID:16580685 PMID:16785445

    Open questions at the time
    • Quantitative contribution of autoinhibition to basal control unclear
    • How specific ligands tip the equilibrium not fully resolved
  6. 2013 High

    Demonstrating that dimerization drives cis-autophosphorylation specifically at Thr-446 ordered the activation steps mechanistically.

    Evidence Yeast genetic system with bypass and dimerization-interface mutants and eIF2α phosphorylation readouts; FRET dimerization assay distinguishing activating vs non-activating RNAs (2015)

    PMID:21978664 PMID:24338483 PMID:26488609

    Open questions at the time
    • Kinetics of dimer-to-phosphorylation transition in cells incompletely defined
    • Alternative inactive dimer states only partially characterized
  7. 2004 High

    Separating kinase-independent NF-κB survival signaling from kinase-dependent eIF2α-mediated death established PKR as a temporal apoptotic switch and a node beyond translation control.

    Evidence Kinase-dead mutants with NF-κB reporter and apoptosis assays; TLR4-IRF3 apoptosis epistasis in macrophages

    PMID:14749731 PMID:15029200

    Open questions at the time
    • Direct NF-κB activation mechanism not molecularly defined
    • How the same kinase routes to survival vs death contextually unresolved
  8. 2003 High

    Placing PKR upstream of the MAPK ribotoxic stress response connected dsRNA-independent stress to JNK/p38/ERK and apoptosis.

    Evidence PKR-deficient (antisense) cells and inhibitor pretreatment with MAPK and apoptosis readouts; chondrocyte PKC/NADPH-oxidase cascade

    PMID:12773753 PMID:28869834

    Open questions at the time
    • Direct PKR substrates linking to MAPK activation not identified
    • Distinction from eIF2α-dependent effects incomplete
  9. 2012 High

    Linking PKR physically and functionally to inflammasome assembly extended its role into innate cytokine output, though the directionality of this control was later contested.

    Evidence Co-IP with NLRP3/NLRP1/NLRC4/AIM2/ASC, cell-free reconstitution, and KO with cytokine readouts (2012) versus kinase-dead/null knock-in mice showing kinase activity represses NLRP3 (2016)

    PMID:22801494 PMID:26794869

    Open questions at the time
    • The 2012 promoting role and 2016 repressing role are not reconciled
    • Context-dependence (priming vs assembly) not fully delineated
  10. 2012 High

    Identifying competing protein regulators (STAT3, PACT/PRKRA, ADAR1, APOBEC3B-PABPC1) defined how PKR's activation threshold is tuned in the absence of pathogen.

    Evidence Recombinant pull-downs, domain-mapping, Co-IP with mutagenesis, genetic rescue/epistasis, and in vivo triple-mutant mouse rescue

    PMID:16785445 PMID:23221979 PMID:29429924 PMID:36781883 PMID:37797622 PMID:39146181

    Open questions at the time
    • Hierarchy and competition among regulators in vivo not quantified
    • Cell-type-specific dominance of inhibitors vs activators unresolved
  11. 2014 High

    Showing that endogenous dsRNAs (inverted-Alu repeats during mitosis, mitochondrial dsRNA) activate PKR established a self-RNA sensing role with cell-cycle and tissue-injury consequences.

    Evidence RNAi/dominant-negative with cell-cycle readouts; fCLIP-seq of mt-dsRNA; PNPT1-KO and PKR-inhibitor renal injury rescue in mice

    PMID:24939934 PMID:30174290 PMID:36869030

    Open questions at the time
    • Triggers gating self-RNA exposure not fully mapped
    • Phosphatase counter-regulation of mt-dsRNA-driven PKR only partly characterized
  12. 2018 High

    Identifying α-synuclein Ser-129 as a direct PKR substrate expanded the kinase's substrate repertoire beyond eIF2α into neurodegeneration-relevant biology.

    Evidence In vitro kinase-substrate assay plus loss- and gain-of-function across multiple cell models and brain slices

    PMID:29501855

    Open questions at the time
    • In vivo contribution to synucleinopathy not established here
    • Whether activation route differs from canonical dsRNA sensing unclear
  13. 2019 Medium

    Discovering ligand-driven PKR cytosolic condensates (dRIFs/clusters) added a spatial layer in which clustering organizes activation yet buffers downstream eIF2α phosphorylation.

    Evidence Live-cell imaging, co-localization, and cluster-disruption phosphorylation assays; G3BP1/cGAS condensation coupling

    PMID:31772125 PMID:35522180 PMID:35939694

    Open questions at the time
    • Single-lab imaging-based mechanism awaits orthogonal validation
    • Molecular determinants of condensate assembly and dissolution undefined
  14. 2020 Medium

    Bidirectional EIF2AK2 disease variants demonstrated that both excess and deficient kinase activity are pathogenic, linking eIF2α-phosphorylation dosage to human neurological disease.

    Evidence Patient-derived fibroblast and transfection eIF2α-phosphorylation assays for gain-of-function (dystonia) and loss-of-function (neurodevelopmental syndrome) variants

    PMID:32197074 PMID:33236446

    Open questions at the time
    • Mechanism connecting altered kinase output to specific phenotypes unresolved
    • Single-lab functional characterization with limited mechanistic depth

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PKR discriminates self from non-self dsRNA in vivo, and how condensate dynamics, competing regulators, and contradictory inflammasome roles are integrated into a unified activation set-point, remains unresolved.
  • No quantitative model reconciling promoting vs repressing inflammasome roles
  • Spatial condensate control of signaling lacks structural mechanism
  • Self-RNA gating thresholds not defined across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
ADAR1ASCEIF2S1G3BP1NLRP3PRKRASTAT3TRAF6
Complex memberships
NLRP3 inflammasome

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PKR is activated by binding to dsRNA via a mechanism involving autophosphorylation, which then phosphorylates the alpha subunit of eIF2 (eIF2α) to inhibit translation initiation. In vitro kinase assays, cell-based assays with dsRNA activation Oncogene High 10557102
1999 HCV envelope protein E2 contains a sequence identical to phosphorylation sites of PKR and eIF2α, and directly inhibits PKR kinase activity, blocking its inhibitory effect on protein synthesis and cell growth. In vitro kinase assay, cell-based protein synthesis and growth inhibition assays Science High 10390359
2008 PKR activation by dsRNA requires dimerization: a minimal dsRNA of 30 bp is required to bind two PKR monomers and elicit autophosphorylation; PKR monomers sequentially attach to a single dsRNA and dimerize via kinase domain contacts. Sedimentation velocity analytical ultracentrifugation, autophosphorylation assays with dsRNAs of defined length Journal of molecular biology High 18599071
2006 PKR activation by dsRNA or the cellular protein PACT involves an intramolecular interaction between a PACT-binding motif (PBM) in the kinase domain and the dsRNA-binding domain that keeps PKR inactive; disruption of this interaction by point mutations produces constitutively active PKR. Biochemical assays, NMR analyses, point mutagenesis, genetic complementation Proceedings of the National Academy of Sciences of the United States of America High 16785445
2005 Crystal structures of eIF2α bound to PKR reveal that PKR forms a back-to-back parallel dimer essential for kinase activation, and demonstrate how eIF2α docks to its kinase; activation-loop phosphorylation allosterically couples dimerization and substrate recognition interfaces. X-ray crystallography, mutagenesis analysis Cell High 16179248
2013 PKR activation requires dimerization-induced cis-phosphorylation at Thr-446 in the activation loop; dimerization precedes and stimulates activation loop autophosphorylation, and these two processes are mutually exclusive yet interdependent. Yeast Saccharomyces cerevisiae model system, PKR bypass mutants, mutagenesis of dimerization-essential residues (Asp-266, Tyr-323), eIF2α phosphorylation assays The Journal of biological chemistry High 24338483
2009 RNA dimerization promotes PKR dimerization and activation: TAR RNA dimers (effectively doubling dsRNA length from 23 bp to ~46 bp) bind two or three PKR molecules and activate PKR, whereas TAR monomers bind only one PKR monomer and do not activate it. Native gel electrophoresis, analytical ultracentrifugation, autophosphorylation assays, enzymatic structure mapping Journal of molecular biology High 19445956
2011 Heparin activates PKR by binding to the kinase domain (not the dsRNA-binding domain) and allosterically enhancing PKR dimerization, demonstrating that PKR can be activated by non-RNA molecules via the kinase domain. Analytical ultracentrifugation, autophosphorylation assays, thermodynamic linkage modeling Journal of molecular biology High 21978664
2015 Activating dsRNAs induce a back-to-back parallel PKR kinase dimer required for activation, whereas non-activating RNAs (e.g., containing a 2'-O-methyl barrier) either fail to induce dimerization or produce an alternative inactive dimer configuration. homo-FRET assay for kinase domain dimerization, autophosphorylation assays, mutagenesis of dimer interface residues Biochemistry High 26488609
2006 Viral inhibitor RNAs EBER(I) (Epstein-Barr virus) and VA(I) (adenovirus) bind PKR dsRNA-binding domains using similar surfaces as activating RNAs but inhibit PKR activation; regions beyond the stem-loop dsRBD contacts are required for inhibition, demonstrating that dsRNA binding and kinase inactivation are non-equivalent. Isothermal titration calorimetry, gel electrophoresis binding assays, NMR chemical shift perturbation, autophosphorylation assays Journal of molecular biology High 16580685
2012 PKR physically interacts with inflammasome components NLRP3, NLRP1, NLRC4, AIM2, and ASC; PKR autophosphorylation in a cell-free reconstituted system with recombinant NLRP3, ASC, and pro-caspase-1 reconstitutes inflammasome activity, and PKR deficiency severely impairs inflammasome activation and IL-1β/IL-18/HMGB1 secretion. Co-immunoprecipitation, cell-free reconstitution with recombinant proteins, genetic deletion, pharmacological inhibition, in vivo peritonitis model Nature High 22801494
2004 PKR is a critical mediator of macrophage apoptosis downstream of TLR4; TLR4-activated PKR promotes apoptosis through inhibition of protein synthesis and activation of interferon response factor 3 (IRF3). Genetic deletion of PKR, epistasis analysis, macrophage apoptosis assays with bacterial pathogens Nature High 15029200
2014 During mitosis, PKR is activated in uninfected cells by binding to dsRNAs formed by inverted Alu repeats (IRAlus) when nuclear structure is disrupted; activated PKR phosphorylates eIF2α to suppress global translation, acts as upstream kinase for JNK, and regulates levels of mitotic factors (cyclins A/B, Polo-like kinase 1) and histone H3 phosphorylation. RNAi knockdown, dominant-negative PKR expression, immunofluorescence, Western blot, cell cycle analysis, RNA pulldown Genes & development High 24939934
2018 PKR interacts with endogenous mitochondrial dsRNAs (mt-dsRNAs) formed by bidirectional transcription of the mitochondrial genome; these mt-dsRNAs regulate PKR and eIF2α phosphorylation to control cell signaling and translation; PKR phosphatases counteract mt-dsRNA-driven PKR activation. Formaldehyde-mediated crosslinking and immunoprecipitation sequencing (fCLIP-seq), Western blot, genetic manipulation Molecular cell High 30174290
2018 Loss of PRKRA (by mis-splicing caused by TIA1/TIAL1 double knockout) triggers EIF2AK2/PKR activation and stress granule formation; ectopic expression of PRKRA cDNA or knockout of EIF2AK2 in double-knockout cells rescues this phenotype, placing PRKRA as a direct upstream regulator of PKR. Double knockout cell lines, PAR-CLIP, Western blot, genetic rescue experiments Molecular cell High 29429924
2012 Cytoplasmic STAT3 directly interacts with EIF2AK2/PKR via the catalytic domain of PKR and the SH2 domain of STAT3 (recapitulated with recombinant proteins in pull-down); STAT3 acts as a competitive inhibitor of PKR-mediated eIF2α phosphorylation; disruption of this complex by STAT3 inhibitors or fatty acids (palmitate) activates PKR-dependent autophagy. Recombinant protein pull-down, Co-IP, overexpression of STAT3 mutants, chemical screen, autophagy flux assays Autophagy High 23221979
2023 ADAR1 dsRBD3 directly interacts with PKR kinase domain on dsRNA to inhibit PKR activation; wild-type or editing-inactive ADAR1 expressed in A549 cells inhibits endogenous PKR, and mutating the ADAR1 dsRBD3-PKR contact prevents co-immunoprecipitation, ADAR1 inhibition of PKR activity, and their co-localization. Co-immunoprecipitation, AlphaFold structural modeling, functional PKR activation assays, mutagenesis of interaction interface, immunofluorescence co-localization Cell reports High 39146181
2023 ADAR1p150 isoform prevents PKR activation through its dsRNA-binding activity (distinct from its RNA-editing function); deleting both MDA5 and PKR completely rescues embryonic lethality of Adar1p150-/- mice, whereas deleting either alone provides limited or no rescue. Genetic epistasis in mice (Adar1p150-/- × Mavs-/- × Eif2ak2-/- triple mutants), survival analysis, genetic rescue experiments Molecular cell High 37797622
2019 Endogenous circRNAs act as PKR inhibitors by forming 16-26 bp imperfect RNA duplexes that suppress PKR activation; upon viral infection or poly(I:C) stimulation, RNase L degrades circRNAs, which is required for PKR activation in early innate immune responses. CircRNA overexpression/depletion, RNase L functional assays, PKR phosphorylation assays, viral infection experiments Cell High 31031002
2010 mRNAs containing uridine activate PKR which phosphorylates eIF2α and inhibits translation; mRNAs with pseudouridine substitutions activate PKR to a lesser degree, bind PKR less efficiently (by RNA pull-down), and are translated equally in PKR knockout cells. RNA pull-down assay, PKR phosphorylation assay, PKR knockout cell translation assay Nucleic acids research High 20457754
2000 Vaccinia virus K3L protein acts as a pseudosubstrate inhibitor of PKR; the K3L protein co-immunoprecipitates with PKR in vaccinia virus-infected cells, and its inhibitory function depends critically on residues near its C-terminus that share a sequence motif with eIF2α. Co-immunoprecipitation in infected cells, yeast growth inhibition assay, cell-free translation assay, mutagenesis Virology High 11040133
2008 Positive selection of specific residues near the eIF2α-binding site on the C-terminal lobe of PKR kinase domain governs sensitivity to poxviral pseudosubstrate inhibitors; substitution of positively selected residues altered species-specific sensitivity to K3L and related poxviral inhibitors without impairing eIF2α phosphorylation. Evolutionary analysis, site-directed mutagenesis, yeast-based PKR function assay, in vitro kinase assay Nature structural & molecular biology High 19043413
2008 Mutations in the C-terminal lobe of the PKR kinase domain confer resistance to vaccinia K3L pseudosubstrate inhibitor (e.g., PKR-D486V shows ~15-fold decreased K3L binding) while leaving eIF2α phosphorylation intact, mapping the eIF2α-binding site to an extensive face of the C-terminal lobe. Yeast-based PKR toxicity screen, in vitro kinase assay, binding affinity measurements Proceedings of the National Academy of Sciences of the United States of America High 18971339
2002 HCV NS5A protein colocalizes with PKR and suppresses dsRNA activation of PKR during HCV RNA replication; mutations in the PKR-binding domain of NS5A relieved this blockade, resulting in IRF-1 activation and reduced HCV replication. Colocalization studies, PKR activation assays, NS5A mutagenesis, HCV replicon system, IRF-1 reporter assays Proceedings of the National Academy of Sciences of the United States of America High 11904369
2004 PKR acts as a molecular clock: its catalysis-independent activity activates NF-κB survival signaling to delay apoptosis, while its kinase activity (phosphorylation of eIF2α) subsequently induces cell death, temporally separating survival and death programs. Kinase-dead PKR mutants, NF-κB reporter assays, apoptosis assays, eIF2α phosphorylation measurements The EMBO journal High 14749731
2003 PKR is a critical upstream mediator of the ribotoxic stress response: DON (deoxynivalenol) rapidly induces PKR autophosphorylation and eIF2α phosphorylation within 1-5 min, and PKR deficiency (via antisense expression) markedly suppresses downstream MAPK (JNK > p38 > ERK) phosphorylation and apoptosis. PKR inhibitor pretreatment, antisense PKR stable transformants, MAPK phosphorylation assays, apoptosis assays Toxicological sciences High 12773753
2018 PKR directly binds and phosphorylates monomeric and filamentous α-synuclein on Ser129 in vitro; overexpression of constitutively active PKR increases Ser129 α-synuclein phosphorylation, while inhibition/knockdown of PKR reduces it in multiple cell models and primary neurons. In vitro phosphorylation assay, PKR inhibitor treatment, PKR siRNA knockdown, PKR overexpression, multiple cell models and acute brain slices Neurobiology of disease High 29501855
2022 PKR forms cytosolic condensates (dsRNA-induced foci, dRIFs) in response to increased endogenous or exogenous dsRNA; dRIFs contain dsRNA, enrich dsRNA-binding proteins (ADAR1, Stau1, NLRP1, PACT), form before translation repression, and localize to regions where PKR activation is initiated; disruption of PKR clusters enhances eIF2α phosphorylation. Live-cell imaging, immunofluorescence, co-localization studies, eIF2α phosphorylation assays, dsRNA length-dependence experiments Proceedings of the National Academy of Sciences of the United States of America Medium 35939694
2022 PKR signaling involves assembly of dynamic PKR clusters driven by ligand binding and front-to-front interfaces between kinase domains; eIF2α is not recruited to PKR clusters, and PKR cluster disruption enhances eIF2α phosphorylation, suggesting clusters buffer downstream signaling. Live-cell fluorescence microscopy, genetic manipulation, eIF2α phosphorylation assays The Journal of cell biology Medium 35522180
2016 PKR kinase activity represses (not activates) cryopyrin/NLRP3 inflammasome activity by inhibiting protein translation of inflammasome constituents to prevent initial priming during innate immune signaling, as demonstrated by a knock-in mouse expressing kinase-dead PKR. Kinase-dead knock-in mouse, PKR-null mouse, inflammasome activation assays, translation inhibition measurements Cell research High 26794869
2013 PKR is activated by CD40 ligation via TRAF6 and TRAF2: TRAF6 co-immunoprecipitates with PKR upon CD40 ligation, TRAF2 bridges TRAF6 and PKR, and PKR activation promotes autophagy and LC3 accumulation around Toxoplasma gondii vacuoles for parasite killing. Co-immunoprecipitation, TRAF2-deficient cells, PKR-null mice, autophagy assays, vacuole-lysosomal fusion assays, parasite killing assays PLoS pathogens High 23990781
2019 PKR promotes G3BP1 foci formation via an RNA-dependent association, which is necessary for cGAS condensation and cGAS-dependent interferon responses to intracellular DNA. Co-immunoprecipitation, loss-of-function (G3BP1 and PKR knockdown), interferon response assays, immunofluorescence Science signaling Medium 31772125
2020 RAN translation from structured CAG, CCUG, CAGG, and G4C2 expansion RNAs is regulated by PKR; blocking PKR via dominant-negative PKR-K296R, TRBP overexpression, or PKR-KO reduces RAN protein levels; inhibiting PKR in C9orf72 BAC transgenic mice with AAV-PKR-K296R or metformin decreases RAN proteins and improves behavior. PKR-KO cells, dominant-negative PKR expression, PKR inhibitors, in vivo AAV delivery, C9orf72 BAC transgenic mouse model Proceedings of the National Academy of Sciences of the United States of America High 32690681
2022 EIF2AK2/PKR bridges YTHDF3 and eIF3A, enhancing the stability of the YTHDF3/eIF3A complex in oxaliplatin-resistant colorectal cancer cells to facilitate translation of m6A-methylated mRNAs. Co-immunoprecipitation, Western blot, functional translation assays ACS chemical biology Low 35708211
2022 Berberine directly binds EIF2AK2 (via two ionic bonds by chemoproteomic analysis), subtly inhibits EIF2AK2 dimerization rather than its enzyme activity, and selectively modulates downstream JNK, NF-κB, AKT, and NLRP3 pathways; EIF2AK2 knockdown attenuates berberine's anti-inflammatory effects in vivo. Chemoproteomic target identification, binding affinity measurements, EIF2AK2 knockdown mice, cytokine assays, dimerization assays Acta pharmaceutica Sinica B Medium 37250154
2023 APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances PKR-suppressing activity of ADAR1 during viral infection, promoting translational blockage and stress granule formation; APOBEC3B localizes to stress granules through its interaction with PABPC1. Co-immunoprecipitation, loss-of-function studies, eIF2α phosphorylation assays, stress granule imaging, viral infection experiments Nature communications Medium 36781883
2024 EIF2AK2 directly targets and positively regulates AIM2 expression; Co-IP demonstrates direct binding between EIF2AK2 and AIM2, and EIF2AK2 induces PANoptosis through upregulating AIM2 in LPS-treated renal tubular cells. Co-immunoprecipitation, Western blot, siRNA knockdown, LPS-stimulated cell model Renal failure Low 39311631
2023 Reduction of PNPT1 leads to leakage of mitochondrial dsRNA into cytoplasm where it activates PKR, causing eIF2α phosphorylation and translational arrest leading to renal tubular atrophy; inhibiting PKR rescues ischemia-reperfusion or ureteral obstruction-induced renal tubular injury in mice. PNPT1 knockout mice, PKR inhibitor treatment, Western blot, in vivo mouse models, histopathology Nature communications High 36869030
2021 Human DICER helicase domain directly interacts with PKR (enriched by proteomics during viral infection); deletion of the DICER helicase domain confers antiviral properties in an RNAi-independent, PKR-dependent manner. Proteomics/interactome analysis, domain-deletion mutants, viral replication assays, PKR-dependency genetic experiments PLoS pathogens Medium 33984068
2020 EIF2AK2 missense variants (p.Gly130Arg, p.Gly138Ala, p.Asn32Thr) found in dystonia patients show abnormally enhanced PKR-mediated phosphorylation of eIF2α in patient-derived fibroblasts, demonstrating gain-of-function kinase activity. Patient-derived fibroblast studies, Western blot for eIF2α phosphorylation, Sanger sequencing Annals of neurology Medium 33236446
2020 EIF2AK2 missense variants associated with neurodevelopmental syndrome show reduced kinase activity in mammalian cell lines and proband-derived fibroblasts, linking deficient eIF2α phosphorylation to the disease phenotype. Mammalian cell line transfection, patient-derived fibroblast functional assays, Western blot for eIF2α phosphorylation American journal of human genetics Medium 32197074
2017 PKR activation in TNF-α-stimulated chondrocytes triggers PKC phosphorylation, which activates NADPH oxidase leading to oxidative stress; this cascade activates COX-2 and IL-8 via ERK/NF-κB pathway and impedes PPAR-γ-mediated inhibition of MMP-13. PKR activation with poly(I:C), PKR/PKC pathway inhibitors, Western blot, NADPH oxidase activity assay, OA patient cartilage Redox biology Medium 28869834
2012 In PKR-null colonic epithelial cells during DSS colitis, eIF2α phosphorylation-mediated unfolded protein response (UPR), ER chaperone response, ERAD, and antioxidative stress response are impaired, as are STAT3 and AKT phosphorylation, demonstrating PKR's role in coordinating multiple pro-survival signaling pathways in epithelial cells. PKR-null mice with bone marrow reconstitution, DSS colitis model, Western blot for pathway components Inflammatory bowel diseases Medium 22275310
1993 The PRKR (EIF2AK2) gene was mapped to human chromosome 2p21-p22 and mouse chromosome 17 E2 using somatic cell hybrids and fluorescence in situ hybridization. Somatic cell hybrid panel, fluorescence in situ hybridization (FISH) Genomics High 7686883 7686884

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 PKR; a sentinel kinase for cellular stress. Oncogene 669 10557102
2019 Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity. Cell 668 31031002
2006 Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiology and molecular biology reviews : MMBR 653 17158706
2012 Novel role of PKR in inflammasome activation and HMGB1 release. Nature 640 22801494
1999 Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science (New York, N.Y.) 579 10390359
2010 Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic acids research 526 20457754
2007 The dsRNA protein kinase PKR: virus and cell control. Biochimie 524 17451862
2001 Signal integration via PKR. Science's STKE : signal transduction knowledge environment 314 11752661
2000 Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action. Apoptosis : an international journal on programmed cell death 304 11232238
2004 The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 299 15029200
2019 PKR: A Kinase to Remember. Frontiers in molecular neuroscience 219 30686999
1995 PKR: a new name and new roles. Trends in biochemical sciences 207 7631421
2018 PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs. Molecular cell 200 30174290
2006 Inhibition of PKR by RNA and DNA viruses. Virus research 174 16704884
2008 Mechanism of PKR Activation by dsRNA. Journal of molecular biology 172 18599071
1999 PKR, apoptosis and cancer. The international journal of biochemistry & cell biology 166 10216948
1997 PKR--a protein kinase regulated by double-stranded RNA. The international journal of biochemistry & cell biology 161 9375375
2022 CircRNA-CREIT inhibits stress granule assembly and overcomes doxorubicin resistance in TNBC by destabilizing PKR. Journal of hematology & oncology 157 36038948
2002 Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proceedings of the National Academy of Sciences of the United States of America 139 11904369
2021 RNA circles with minimized immunogenicity as potent PKR inhibitors. Molecular cell 136 34951963
2003 Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicological sciences : an official journal of the Society of Toxicology 133 12773753
2006 Activation of PKR: an open and shut case? Trends in biochemical sciences 124 17196820
2014 PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator. Genes & development 122 24939934
2010 Regulation of innate immunity through RNA structure and the protein kinase PKR. Current opinion in structural biology 114 21145228
2020 Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proceedings of the National Academy of Sciences of the United States of America 113 32690681
2005 PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking. Cell 111 16179248
2006 Molecular basis for PKR activation by PACT or dsRNA. Proceedings of the National Academy of Sciences of the United States of America 110 16785445
2008 Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nature structural & molecular biology 107 19043413
2009 Activation of the Antiviral Kinase PKR and Viral Countermeasures. Viruses 100 21994559
2018 The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression. Molecular cell 96 29429924
2004 The protein kinase PKR: a molecular clock that sequentially activates survival and death programs. The EMBO journal 91 14749731
2014 The impact of PKR activation: from neurodegeneration to cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 85 24522206
2012 PKR-dependent inflammatory signals. Science signaling 85 23092889
2023 ADAR1p150 prevents MDA5 and PKR activation via distinct mechanisms to avert fatal autoinflammation. Molecular cell 83 37797622
1996 The regulation of the protein kinase PKR by RNA. Biochimie 81 9150867
2008 PERK and PKR: old kinases learn new tricks. Cell cycle (Georgetown, Tex.) 78 18418049
2021 Inhibition of PKR by Viruses. Frontiers in microbiology 77 34759908
2011 Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity. The Journal of biological chemistry 72 21636578
2009 RNA dimerization promotes PKR dimerization and activation. Journal of molecular biology 70 19445956
2022 Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects. Acta pharmaceutica Sinica. B 67 37250154
1997 The PKR protein kinase--an interferon-inducible regulator of cell growth and differentiation. International journal of hematology 66 9114594
2017 PKR involvement in Alzheimer's disease. Alzheimer's research & therapy 64 28982375
2010 Multiple levels of PKR inhibition during HIV-1 replication. Reviews in medical virology 64 21294215
2004 PKR activation in neurodegenerative disease. Journal of neuropathology and experimental neurology 63 14989595
2020 De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. American journal of human genetics 59 32197074
2021 A tale of two proteins: PACT and PKR and their roles in inflammation. The FEBS journal 57 33387379
2006 Uncoupling of RNA binding and PKR kinase activation by viral inhibitor RNAs. Journal of molecular biology 57 16580685
1994 Proteins that interact with PKR. Biochimie 57 7893827
2022 dsRNA-induced condensation of antiviral proteins modulates PKR activity. Proceedings of the National Academy of Sciences of the United States of America 56 35939694
2019 PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing. Science signaling 55 31772125
2020 EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia. Annals of neurology 54 33236446
2012 Direct interaction between STAT3 and EIF2AK2 controls fatty acid-induced autophagy. Autophagy 52 23221979
2017 PKR activation causes inflammation and MMP-13 secretion in human degenerated articular chondrocytes. Redox biology 51 28869834
2007 PKR in innate immunity, cancer, and viral oncolysis. Methods in molecular biology (Clifton, N.J.) 51 18217692
2013 Activation of protein kinase PKR requires dimerization-induced cis-phosphorylation within the activation loop. The Journal of biological chemistry 49 24338483
2023 Chemotherapy-Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA-Mediated PKR Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 46 36683218
2012 PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling. Inflammatory bowel diseases 43 22275310
2007 Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease. Neurobiology of aging 43 17420072
2022 Viral evasion of PKR restriction by reprogramming cellular stress granules. Proceedings of the National Academy of Sciences of the United States of America 41 35858300
2000 Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients. The Journal of clinical investigation 41 11120763
1993 Chromosomal assignment of the interferon-inducible double-stranded RNA-dependent protein kinase (PRKR) to human chromosome 2p21-p22 and mouse chromosome 17 E2. Genomics 40 7686883
2022 Signaling by the integrated stress response kinase PKR is fine-tuned by dynamic clustering. The Journal of cell biology 39 35522180
2017 PKR induces the expression of NLRP3 by regulating the NF-κB pathway in Porphyromonas gingivalis-infected osteoblasts. Experimental cell research 39 28341446
2023 APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection. Nature communications 37 36781883
2022 YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in Oxaliplatin-Resistant Colorectal Cancer. ACS chemical biology 37 35708211
2000 Pseudosubstrate inhibition of protein kinase PKR by swine pox virus C8L gene product. Virology 37 11040133
2015 PKR downregulation prevents neurodegeneration and β-amyloid production in a thiamine-deficient model. Cell death & disease 36 25590804
2018 Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death. Neurobiology of disease 35 29501855
2015 Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors. Molecular medicine (Cambridge, Mass.) 35 26052716
2016 The kinase activity of PKR represses inflammasome activity. Cell research 33 26794869
2008 Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L protein. Proceedings of the National Academy of Sciences of the United States of America 33 18971339
2018 ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication. Cytokine & growth factor reviews 32 29625900
2016 nc886, a non-coding RNA and suppressor of PKR, exerts an oncogenic function in thyroid cancer. Oncotarget 32 27612419
2001 PACT and PKR: turning on NF-kappa B in the absence of virus. Science's STKE : signal transduction knowledge environment 31 11752660
2020 Hepatitis C virus exploits cyclophilin A to evade PKR. eLife 30 32539931
2018 Novel role of PKR in palmitate-induced Sirt1 inactivation and endothelial cell senescence. American journal of physiology. Heart and circulatory physiology 30 29906232
2017 Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism. Expert reviews in molecular medicine 30 28724458
2013 The protein kinase double-stranded RNA-dependent (PKR) enhances protection against disease cause by a non-viral pathogen. PLoS pathogens 29 23990781
2011 Heparin activates PKR by inducing dimerization. Journal of molecular biology 29 21978664
2009 Tipping the balance: antagonism of PKR kinase and ADAR1 deaminase functions by virus gene products. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 29 19715457
1998 RNA binding and modulation of PKR activity. Methods (San Diego, Calif.) 29 9735304
2021 EIF2AK2 selectively regulates the gene transcription in immune response and histones associated with systemic lupus erythematosus. Molecular immunology 28 33588244
2023 Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis. Nature communications 27 36869030
2000 A new double-stranded RNA-binding protein that interacts with PKR. Nucleic acids research 27 10684936
1993 Localization of the human interferon-induced, ds-RNA activated p68 kinase gene (PRKR) to chromosome 2p21-p22. Genomics 27 7686884
2016 PKR promotes choroidal neovascularization via upregulating the PI3K/Akt signaling pathway in VEGF expression. Molecular vision 26 27994435
2015 NIPBL Controls RNA Biogenesis to Prevent Activation of the Stress Kinase PKR. Cell reports 26 26725122
2000 Tissue specific expression of PKR protein kinase in aging B6D2F1 mice. Mechanisms of ageing and development 26 10799709
2024 EIF2AK2 protein targeted activation of AIM2-mediated PANoptosis promotes sepsis-induced acute kidney injury. Renal failure 25 39311631
2014 HIV-1 translation and its regulation by cellular factors PKR and PACT. Virus research 25 25064266
2024 An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation. Cell reports 24 39146181
2021 Human DICER helicase domain recruits PKR and modulates its antiviral activity. PLoS pathogens 24 33984068
2019 The Leader Protein of Theiler's Virus Prevents the Activation of PKR. Journal of virology 24 31292248
2018 The Noncoding RNA nc886 Regulates PKR Signaling and Cytokine Production in Human Cells. Journal of immunology (Baltimore, Md. : 1950) 24 30518569
2015 Regulation of PKR by RNA: formation of active and inactive dimers. Biochemistry 24 26488609
2017 Interaction of PKR with single-stranded RNA. Scientific reports 23 28611419
2016 Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition. Biomarkers in cancer 22 27486347
2012 Activation of PKR by RNA misfolding: HDV ribozyme dimers activate PKR. RNA (New York, N.Y.) 22 23105000
2022 PKR and TLR3 trigger distinct signals that coordinate the induction of antiviral apoptosis. Cell death & disease 21 35970851
2003 Transcriptional upregulation of interferon-induced protein kinase, PKR, in breast cancer. Cancer letters 21 12860279

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