Affinage

EIF2AK2

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

Length
551 aa
Mass
62.1 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2AK2 (PKR) is an interferon-induced serine/threonine kinase that serves as a central cytoplasmic sensor of double-stranded RNA, integrating pathogen detection, endogenous RNA surveillance, and cellular stress into translational control, innate immune signaling, and cell fate decisions. Activation occurs when dsRNA (≥30 bp) or the stress-responsive protein PACT binds the N-terminal dsRNA-binding domain, relieving an autoinhibitory intramolecular interaction between the dsRBD and kinase domain, thereby promoting kinase-domain dimerization through a conserved Arg262–Asp266 salt bridge and cis-autophosphorylation of Thr446 in the activation loop, which enables specific phosphorylation of eIF2α on Ser51 to suppress global translation (PMID:16179259, PMID:16785445, PMID:18599071, PMID:17202131, PMID:24338483). PKR is negatively regulated by ADAR1p150 (via direct dsRBD3–kinase domain contact on dsRNA), STAT3 (SH2-domain interaction with the catalytic domain), TRBP, Hsp90/p23, and endogenous circRNA duplexes, while endogenous activating ligands include mitochondrial dsRNAs, inverted Alu repeat transcripts released during mitosis, snoRNAs, and structured repeat expansion RNAs (PMID:39146181, PMID:23084476, PMID:11447118, PMID:31031002, PMID:30174290, PMID:24939934, PMID:25848059, PMID:32690681). Beyond translational control, PKR activates NF-κB both kinase-dependently and kinase-independently through physical interactions with IKKβ and TRAF2/5, promotes inflammasome assembly by interacting with NLRP3/NLRC4/AIM2/ASC, initiates RIP1/RIP3-dependent necroptosis, and forms dsRNA-induced cytoplasmic condensates (dRIFs) that buffer downstream integrated stress response signaling (PMID:10848580, PMID:15121867, PMID:22801494, PMID:23898178, PMID:35939694, PMID:35522180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1999 High

    Establishing that PKR is a dsRNA-activated kinase that phosphorylates eIF2α to inhibit translation and activates NF-κB-dependent inflammatory gene transcription provided the foundational dual-function framework for all subsequent mechanistic dissection.

    Evidence Biochemical assays, in vitro kinase assays, and cell-based studies

    PMID:10557102

    Open questions at the time
    • Mechanism of NF-κB activation not resolved
    • No structural basis for dsRNA-dependent activation
  2. 2000 High

    Demonstrating that PKR activates NF-κB independently of its kinase activity through physical interaction with IKKβ revealed a scaffolding function distinct from its catalytic role.

    Evidence GST pull-down with kinase-dead PKR mutant, NF-κB reporter assay in PKR-null cells

    PMID:10848580

    Open questions at the time
    • Whether kinase-dependent and kinase-independent NF-κB pathways operate simultaneously in vivo
    • Stoichiometry of PKR-IKKβ interaction unknown
  3. 2001 High

    Identifying Hsp90/p23 as a chaperone complex that binds PKR and holds it in a latent state — with dsRNA or Hsp90 inhibitors triggering dissociation and activation — established a negative regulatory mechanism independent of dsRNA-binding competitors.

    Evidence Co-immunoprecipitation, geldanamycin treatment, yeast Hsp90 mutant system

    PMID:11447118

    Open questions at the time
    • Whether Hsp90 regulates PKR stability vs. conformation in vivo
    • Structural basis of Hsp90-PKR interaction unresolved
  4. 2004 High

    Mapping PKR's physical interaction with TRAF2 and TRAF5 via a TRAF-interaction motif in the kinase domain, and showing this is required for NF-κB activation, placed PKR within canonical TNF receptor signaling adaptor networks.

    Evidence Co-immunoprecipitation, TRAF-deficient cell lines, dominant-negative expression

    PMID:15121867

    Open questions at the time
    • Whether TRAF and IKKβ interactions are sequential or alternative
    • Direct ubiquitylation events downstream of PKR-TRAF not characterized
  5. 2005 High

    Resolving that PKR activation requires catalytic-domain dimerization that triggers Thr446 autophosphorylation, and that helix αG mediates specific eIF2α substrate recognition, provided the structural logic for how dsRNA binding translates into kinase activity.

    Evidence Mutagenesis, in vitro kinase assays, yeast growth suppression, pseudosubstrate binding

    PMID:16179259

    Open questions at the time
    • Full-length PKR crystal structure with dsRNA not available
    • Kinetics of dimerization vs. autophosphorylation not quantified
  6. 2006 High

    Two complementary studies established that PKR activation involves both relief of an autoinhibitory intramolecular dsRBD–kinase domain interaction and dsRNA-induced dimerization, showing these are two facets of the same activation mechanism requiring ≥30 bp dsRNA to bridge two PKR monomers.

    Evidence NMR, sedimentation velocity AUC, point mutagenesis, in vitro kinase assays with defined-length dsRNAs

    PMID:16785445 PMID:17196820

    Open questions at the time
    • Whether autoinhibition release and dimerization are obligatorily coupled or separable
    • Dynamics of dsRNA scanning not resolved
  7. 2007 High

    Identifying the conserved Arg262–Asp266 salt bridge at the PKR dimer interface as essential for all eIF2α kinase family members — with charge-swap rescue confirming the contact — generalized the dimerization mechanism across the family.

    Evidence Charge-swap mutagenesis, yeast functional assay, in vitro kinase assay

    PMID:17202131

    Open questions at the time
    • Whether other eIF2α kinases use identical interface geometry
    • Allosteric communication from dimer interface to active site not mapped
  8. 2008 High

    Showing that positively selected residues near PKR's eIF2α binding site confer species-specific sensitivity to poxviral pseudosubstrate inhibitors revealed the evolutionary arms race driving PKR diversification while maintaining substrate specificity.

    Evidence Evolutionary analysis, site-directed mutagenesis, in vitro kinase assays with poxviral inhibitors

    PMID:19043413

    Open questions at the time
    • Whether host-virus co-evolution at this interface drives compensatory eIF2α changes
    • Structural basis of pseudosubstrate vs. true substrate discrimination
  9. 2008 High

    Demonstrating that PACT-mediated PKR activation during ER stress requires stress-induced PACT phosphorylation and direct PACT–PKR interaction, with PACT-null and PKR-null cells resistant to ER stress-induced apoptosis, established PACT as a physiological dsRNA-independent PKR activator coupling ER stress to cell death.

    Evidence PACT/PKR null cell lines, cDNA reconstitution, in vitro interaction assays, apoptosis assays, phosphomimetic mutagenesis

    PMID:19007793 PMID:19580324

    Open questions at the time
    • Identity of the kinase(s) that phosphorylate PACT domain 3 serines under ER stress
    • Whether PACT also induces PKR dimerization or uses a distinct activation mode
  10. 2010 High

    Demonstrating that PKR distinguishes uridine- from pseudouridine-containing mRNA — with pseudouridine preventing PKR binding and activation — revealed a chemical basis for innate immune discrimination of self vs. non-self RNA that later informed mRNA therapeutic design.

    Evidence RNA pull-down, in vitro kinase assay, PKR knockout cell validation

    PMID:20457754

    Open questions at the time
    • Whether other base modifications similarly modulate PKR recognition
    • In vivo stoichiometry of PKR-mRNA encounters not quantified
  11. 2011 High

    Showing that heparin activates PKR by binding the kinase domain (not dsRBD) and allosterically enhancing dimerization identified a structurally distinct, non-RNA activation mode and expanded the repertoire of PKR ligands.

    Evidence Analytical ultracentrifugation, in vitro autophosphorylation, thermodynamic linkage analysis

    PMID:21978664

    Open questions at the time
    • Physiological relevance of heparin-PKR interaction in vivo unclear
    • Structural details of heparin binding site not resolved
  12. 2012 High

    Three studies in 2012 expanded PKR's cellular roles beyond translation: PKR was shown to physically interact with multiple inflammasome sensors (NLRP3, AIM2, NLRC4, ASC) and be required for inflammasome assembly; STAT3 was identified as a direct inhibitor of PKR autophosphorylation; and PKR was linked to p53 sumoylation and cell cycle arrest during ER stress.

    Evidence Cell-free inflammasome reconstitution with PKR KO; recombinant STAT3 pull-down with domain mutants; PKR-null MEFs with sumoylation assays

    PMID:22214662 PMID:22801494 PMID:23084476

    Open questions at the time
    • The 2016 kinase-dead knock-in study contradicted PKR as a positive inflammasome regulator, creating unresolved controversy
    • Direct phosphorylation targets linking PKR to inflammasome assembly not identified
    • Whether STAT3 inhibition of PKR operates in all cell types
  13. 2013 High

    Two findings in 2013 refined the activation mechanism and expanded downstream effectors: dimerization-induced cis-phosphorylation of Thr446 was shown to be the obligate activation step, and PKR was found to interact with RIP1 to initiate necroptosis when caspases are inactive.

    Evidence Engineered bypass mutants in yeast with in vitro kinase assays; Co-IP with PKR-deficient cells and kinase-dead mutants

    PMID:23898178 PMID:24338483

    Open questions at the time
    • Whether PKR directly phosphorylates RIP1 or acts as a scaffold for necrosome formation
    • Structural basis for cis- vs. trans-autophosphorylation not fully resolved
  14. 2014 High

    Discovery that PKR is activated during normal mitosis by inverted Alu repeat dsRNAs released upon nuclear envelope breakdown — suppressing translation and regulating mitotic progression — established a physiological, non-pathogen-related function for PKR in cell division.

    Evidence RNAi knockdown, dominant-negative mutant, dsRNA immunoprecipitation, live-cell imaging, flow cytometry

    PMID:24939934

    Open questions at the time
    • How mitotic PKR activation is terminated after cytokinesis
    • Whether other endogenous dsRNA sensors also respond to IRAlus during mitosis
  15. 2014 High

    Identification of DHX36 as an ATPase/helicase that forms a dsRNA-dependent complex with PKR and facilitates its phosphorylation connected PKR activation to RNA helicase-mediated dsRNA processing and stress granule/RIG-I signaling.

    Evidence Co-immunoprecipitation, DHX36 knockout inducible MEFs, PKR phosphorylation assays

    PMID:24651521

    Open questions at the time
    • Whether DHX36 remodels dsRNA structure to enhance PKR binding or stabilizes the PKR-dsRNA complex
    • Generalizability to other DEAH-box helicases
  16. 2015 High

    Identifying snoRNAs as PKR-binding activators after metabolic stress broadened the endogenous RNA activator repertoire beyond canonical dsRNA and Alu repeats.

    Evidence RIP-Seq, UV crosslinking IP, in vitro PKR activation assay, snoRNA transfection

    PMID:25848059

    Open questions at the time
    • Which snoRNA structural features are sufficient for PKR activation
    • Whether snoRNA-PKR interaction occurs under non-metabolic stress conditions
  17. 2016 High

    Using kinase-dead knock-in and PKR-null mice, a contradictory finding showed that PKR kinase activity represses NLRP3 inflammasome priming by inhibiting translation of inflammasome constituents, directly opposing the 2012 report of PKR as a positive inflammasome activator.

    Evidence Kinase-dead PKR knock-in mouse, PKR-null mouse, inflammasome activity assays

    PMID:26794869

    Open questions at the time
    • Reconciliation of opposing inflammasome findings remains unresolved — may reflect cell type, stimulus, or kinetics differences
    • Whether scaffolding vs. kinase functions of PKR have opposing effects on inflammasome
  18. 2018 High

    Three 2018 studies expanded the network of endogenous PKR regulators: mitochondrial dsRNAs formed by bidirectional transcription were identified as constitutive PKR ligands held in check by phosphatases; stress-induced TRBP phosphorylation was shown to enhance its PKR-inhibitory function; and PACT was placed genetically upstream of PKR in stress granule formation via TIA1/TIAL1 epistasis.

    Evidence fCLIP-seq with functional validation; TRBP phospho-mutant Co-IP; PAR-CLIP with double KO and genetic rescue

    PMID:29348664 PMID:29429924 PMID:30174290

    Open questions at the time
    • Identity of the phosphatases that counteract mtdsRNA-induced PKR activation
    • Whether TRBP and PACT compete for the same PKR binding site
    • Quantitative contribution of mtdsRNA vs. nuclear dsRNA to basal PKR activity
  19. 2019 High

    Endogenous circRNAs were identified as tonic PKR inhibitors through short imperfect dsRNA duplexes, with RNase L-mediated circRNA degradation during viral infection required for PKR derepression — linking circRNA metabolism to innate immune activation and providing a mechanism relevant to SLE autoimmunity.

    Evidence Cellular overexpression/knockdown, RNase L degradation assays, PKR phosphorylation analysis in patient PBMCs

    PMID:31031002

    Open questions at the time
    • Which specific circRNAs are the dominant PKR suppressors in different tissues
    • Whether circRNA-PKR inhibition is stoichiometric or catalytic
  20. 2020 High

    Two findings extended PKR's disease relevance: structured repeat expansion RNAs were shown to activate PKR and promote pathological RAN translation in ALS/FTD models, while de novo EIF2AK2 missense variants causing reduced kinase activity were linked to a neurodevelopmental disorder, establishing PKR as essential for normal brain development.

    Evidence PKR-KO cells and dominant-negative PKR with AAV-mediated inhibition in C9orf72 mice; patient-derived fibroblast kinase assays across multiple probands

    PMID:32197074 PMID:32690681

    Open questions at the time
    • Whether PKR-driven RAN translation is eIF2α-dependent or uses an alternative mechanism
    • Full phenotypic spectrum of EIF2AK2 loss-of-function in humans not defined
    • Whether neurodevelopmental pathology reflects translational control, NF-κB, or other PKR effector arm
  21. 2022 High

    Live-cell imaging revealed that PKR forms dynamic cytoplasmic condensates (dRIFs/clusters) upon dsRNA stimulation that buffer eIF2α phosphorylation — with eIF2α excluded from clusters and cluster disruption enhancing ISR signaling — introducing a phase-separation/clustering layer to PKR regulation.

    Evidence Live-cell imaging, mutagenesis, eIF2α phosphorylation assays, dsRNA stimulation

    PMID:35522180 PMID:35939694

    Open questions at the time
    • Material properties (liquid vs. gel) of dRIFs not characterized
    • Whether dRIF formation occurs at physiological PKR concentrations in primary cells
    • Relationship between dRIFs and canonical stress granules not fully resolved
  22. 2023 High

    In vivo epistasis in triple-knockout mice demonstrated that ADAR1p150 prevents PKR activation via dsRNA binding (editing-independent), while ADAR1 editing prevents MDA5 activation — with combined MDA5/PKR deletion fully rescuing Adar1p150 embryonic lethality — definitively separating ADAR1's editing and PKR-inhibitory functions.

    Evidence Triple knockout mouse genetics, epistasis analysis

    PMID:37797622

    Open questions at the time
    • Whether ADAR1p150 sequesters dsRNA from PKR or directly contacts PKR on dsRNA
    • Tissue-specific contributions of ADAR1-PKR vs. ADAR1-MDA5 axes
  23. 2024 High

    Mapping the direct ADAR1 dsRBD3–PKR kinase domain contact surface on dsRNA — with mutagenesis abolishing interaction, co-localization, and PKR inhibition while editing-inactive ADAR1 retained inhibitory activity — resolved that ADAR1 inhibits PKR through a direct protein-protein interaction on dsRNA rather than by editing away dsRNA substrates.

    Evidence AlphaFold structural modeling, mutagenesis, Co-IP, in vivo/in vitro PKR phosphorylation assays

    PMID:39146181

    Open questions at the time
    • Crystal structure of the ternary ADAR1-dsRNA-PKR complex not yet determined
    • Whether this contact surface is targetable for therapeutic modulation of PKR in autoimmune disease

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of full-length PKR bound to dsRNA; whether PKR's opposing roles in inflammasome regulation reflect cell-type or stimulus-specific contexts; the mechanism by which PKR condensates buffer ISR signaling; and whether PKR's scaffolding vs. kinase functions can be selectively targeted therapeutically.
  • No full-length PKR-dsRNA co-crystal structure
  • Inflammasome promotion vs. repression controversy unresolved
  • Phase separation mechanism and physiological relevance of dRIFs need reconstitution
  • Selective targeting of scaffolding vs. kinase activity not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-392499 Metabolism of proteins 7 R-HSA-162582 Signal Transduction 5 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ADARDHX36EIF2S1IKBKBNLRP3PRKRARIPK1TRAF2

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PKR (EIF2AK2) is autophosphorylated and activated upon binding to dsRNA, leading to phosphorylation of eIF2α and inhibition of protein synthesis; PKR also induces transcription of inflammatory genes via activation of NF-κB and other transcription factors. Biochemical assays, in vitro kinase assays, cell-based studies Oncogene High 10557102
2005 PKR activation requires catalytic-domain dimerization, which triggers Thr446 autophosphorylation within the activation segment; helix αG is critical for specific recognition of eIF2α substrate; mutations on the dimerization surface block autophosphorylation and eIF2α phosphorylation. Mutagenesis, in vitro kinase assays, yeast growth suppression, pseudosubstrate binding Cell High 16179259
2006 PKR activation by dsRNA or PACT is mediated by relief of an intramolecular autoinhibitory interaction between the kinase domain PACT-binding motif (PBM) and the dsRNA-binding domain; disruption of this interaction by mutations or a decoy PBM peptide constitutively activates PKR. NMR, biochemical assays, point mutagenesis, in vitro kinase assays Proceedings of the National Academy of Sciences of the United States of America High 16785445
2006 dsRNA functions primarily to induce dimerization of PKR via the kinase domain rather than solely releasing autoinhibition; a minimum of 30 bp dsRNA is required to bind two PKR monomers and elicit autophosphorylation. Biophysical analyses, sedimentation velocity, in vitro autophosphorylation assays with dsRNAs of varying length Trends in biochemical sciences High 17196820 18599071
2008 PKR requires dsRNA of at least 30 bp to bind two monomers and undergo dimerization-driven autophosphorylation; sequential, non-cooperative attachment of PKR monomers to dsRNA leads to dimerization via the kinase domain. Sedimentation velocity analytical ultracentrifugation, in vitro autophosphorylation assays Journal of molecular biology High 18599071
2007 A conserved intermolecular salt bridge between Arg262 and Asp266 at the PKR kinase domain dimer interface is essential for PKR activity; charge-swap double mutations restore function, confirming this interface is critical for the eIF2α kinase family. Mutagenesis, yeast functional assay, in vitro kinase assay The Journal of biological chemistry High 17202131
2013 PKR activation requires dimerization-induced cis-phosphorylation of Thr446 in the activation loop; dimerization precedes and stimulates activation loop autophosphorylation, and these processes are mutually exclusive yet interdependent. Yeast functional system, engineered bypass mutants, in vitro kinase assays The Journal of biological chemistry High 24338483
2000 PKR activates NF-κB independent of its kinase activity by physically interacting with the IKKβ subunit of the IKK complex, as demonstrated by GST pull-down and catalytically inactive mutant PKR still activating NF-κB. GST pull-down, co-expression of kinase-dead PKR mutants, NF-κB reporter assay, PKR-null cell reconstitution Molecular and cellular biology High 10848580
2004 PKR physically interacts with TRAF2 and TRAF5 via a TRAF-interaction motif in its kinase domain; this interaction is induced by PKR dimerization and is required for PKR-mediated NF-κB activation. Co-immunoprecipitation, confocal colocalization, TRAF-deficient cell lines, dominant-negative expression, computer docking Molecular and cellular biology High 15121867
2012 The SH2 domain of cytoplasmic STAT3 interacts with the catalytic domain of EIF2AK2/PKR to inhibit its activating autophosphorylation; disruption of this interaction (by STAT3 inhibitors or palmitate) leads to PKR-dependent eIF2α phosphorylation and autophagy induction. Recombinant protein pull-down, co-immunoprecipitation, pharmacological/genetic STAT3 inhibition, PKR knockdown, STAT3 domain mutants Molecular cell High 23084476 23221979
2012 PKR is required for inflammasome activation in macrophages; PKR autophosphorylation precedes inflammasome assembly, and PKR physically interacts with NLRP3, NLRP1, NLRC4, AIM2, and ASC. Reconstitution of inflammasome activity in a cell-free system with recombinant NLRP3, ASC, and pro-caspase-1 required PKR autophosphorylation. Co-immunoprecipitation, PKR genetic knockout, pharmacological inhibition, cell-free reconstitution assay Nature High 22801494
2013 IFN-induced PKR interacts with RIP1 to initiate necrosome formation and trigger RIP1/RIP3-mediated necrosis when FADD is absent or caspases are inactivated; PKR kinase activity (not RIP1 kinase activity) is required for this process. Co-immunoprecipitation, PKR-deficient cells, kinase-dead mutants, genetic knockouts, live-cell imaging Proceedings of the National Academy of Sciences of the United States of America High 23898178
2019 Endogenous circRNAs form 16–26 bp imperfect RNA duplexes and act as inhibitors of PKR; upon viral infection, RNase L degrades circRNAs, which is required for PKR activation in innate immune responses. Overexpression of dsRNA-containing circRNA alleviates aberrant PKR activation in SLE patient cells. Cellular overexpression/knockdown, RNase L-mediated degradation assays, PKR phosphorylation analysis, patient PBMCs Cell High 31031002
2010 PKR is activated by uridine-containing in vitro transcribed mRNA but not by pseudouridine-containing mRNA; PKR binds uridine-containing mRNA more efficiently, and pseudouridine substitution reduces PKR activation and diminishes eIF2α-mediated translation inhibition. RNA pull-down, in vitro kinase assay, PKR knockout cell validation Nucleic acids research High 20457754
2014 PKR is activated during mitosis in uninfected cells by binding to dsRNAs formed by inverted Alu repeats (IRAlus) that become accessible when nuclear structure breaks down; activated pPKR suppresses global translation via eIF2α phosphorylation and regulates JNK, cyclin A/B, PLK1 levels, and histone H3 phosphorylation; PKR disruption causes cytokinesis defects. RNAi knockdown, dominant-negative mutant expression, immunoprecipitation of dsRNA, live-cell imaging, flow cytometry Genes & development High 24939934
2018 PKR interacts with endogenous mitochondrial RNAs (mtRNAs) that form intermolecular dsRNAs due to bidirectional transcription; these mtRNAs regulate PKR and eIF2α phosphorylation; PKR activation by mtRNAs is counteracted by PKR phosphatases, and disruption of phosphatases causes apoptosis. Formaldehyde crosslinking and immunoprecipitation sequencing (fCLIP-seq), RNAi knockdown, PKR phosphorylation assays Molecular cell High 30174290
2001 The Hsp90 chaperone complex (Hsp90 and co-chaperone p23) binds to PKR through both its N-terminal dsRNA-binding region and kinase domain; dsRNA or Hsp90 inhibitors (geldanamycin, radicicol) rapidly dissociate Hsp90/p23 from PKR and activate it, triggering eIF2α phosphorylation. Co-immunoprecipitation, geldanamycin treatment, in vivo and in vitro PKR activation assays, yeast Hsp90 mutant system The EMBO journal High 11447118
2009 Stress-induced phosphorylation of specific serine residues in domain 3 of PACT increases its affinity for PKR, leading to PKR autophosphorylation and eIF2α phosphorylation; phosphomimetic aspartate substitutions at these serines enhance PACT-PKR binding and PKR activation in vitro. In vitro binding assays, in vitro kinase assays, phosphomimetic mutagenesis Biochemistry High 19580324
2008 PACT-mediated PKR activation via direct protein-protein interaction is essential for ER stress-induced apoptosis; PACT is phosphorylated in response to tunicamycin and activates PKR; PACT-null and PKR-null cells are resistant to ER stress-induced apoptosis with defective eIF2α phosphorylation. PACT/PKR null cell lines, reconstitution with cDNA, in vitro interaction assays, apoptosis assays Journal of molecular biology High 19007793
2011 Heparin activates PKR by binding to the kinase domain (not the dsRNA-binding domain) and allosterically enhancing PKR dimerization, leading to autophosphorylation; heparin hexasaccharides are sufficient for activation. Analytical ultracentrifugation, in vitro autophosphorylation assays, thermodynamic linkage analysis Journal of molecular biology High 21978664
2015 Small nucleolar RNAs (snoRNAs) interact with PKR after metabolic stress (palmitic acid treatment) via its dsRNA-binding domain; a subset of snoRNAs can bind and activate PKR in vitro, and snoRNA transfection activates PKR in cells. RIP-Seq, UV crosslinking immunoprecipitation with RT-qPCR, in vitro PKR activation assay, snoRNA transfection Proceedings of the National Academy of Sciences of the United States of America High 25848059
2014 DHX36 forms a complex with PKR in a dsRNA-dependent manner and facilitates dsRNA binding and phosphorylation of PKR through its ATPase/helicase activity, thereby promoting antiviral stress granule formation and RIG-I signaling. Co-immunoprecipitation, DHX36 knockout inducible MEF cells, PKR phosphorylation assays PLoS pathogens High 24651521
2018 Loss of PRKRA (PACT) by mis-splicing in TIA1/TIAL1 double-knockout cells triggers EIF2AK2/PKR activation and stress granule formation; ectopic PRKRA cDNA or EIF2AK2 knockout rescues this phenotype, placing PRKRA upstream of EIF2AK2 in RNA stress sensing. PAR-CLIP, double gene knockout, genetic rescue with cDNA or knockout Molecular cell High 29429924
2008 Positively selected residues in the PKR kinase domain near the eIF2α binding site confer species-specific differences in sensitivity to poxviral pseudosubstrate inhibitors; substitution of these residues alters inhibitor sensitivity while maintaining eIF2α phosphorylation activity. Evolutionary analysis, site-directed mutagenesis, in vitro kinase assays with poxviral inhibitors Nature structural & molecular biology High 19043413
2022 PKR forms dynamic cytosolic condensates (dsRNA-induced foci, dRIFs) in response to elevated dsRNA; dRIFs contain dsRNA and enriched dsRNA-binding proteins (ADAR1, Stau1, NLRP1, PACT); dRIF formation correlates with and precedes PKR activation and translation repression, and dRIF disruption enhances eIF2α phosphorylation. Live-cell imaging, immunofluorescence, eIF2α phosphorylation assays, dsRNA stimulation Proceedings of the National Academy of Sciences of the United States of America High 35939694
2022 PKR signaling involves assembly of dynamic PKR clusters driven by ligand binding to the sensor domain and front-to-front interfaces between kinase domains; eIF2α is excluded from PKR clusters, and cluster disruption enhances eIF2α phosphorylation, suggesting clustering buffers downstream ISR signaling. Live-cell imaging, mutagenesis, eIF2α phosphorylation assays, proximity-based approaches The Journal of cell biology Medium 35522180
2023 ADAR1p150 cytoplasmic isoform prevents PKR activation via its dsRNA-binding activity (editing-independent mechanism), while ADAR1 RNA editing prevents MDA5 activation; deleting both MDA5 and PKR fully rescues embryonic lethality of Adar1p150-/- mice. Triple knockout mouse genetics, epistasis analysis Molecular cell High 37797622
2024 ADAR1 dsRBD3 directly interacts with the PKR kinase domain on dsRNA to inhibit PKR activation; AlphaFold modeling and mutagenesis of the ADAR1 dsRBD3–PKR contact surface abolish co-immunoprecipitation, PKR inhibition, and co-localization; editing-inactive ADAR1 retains PKR-inhibitory activity but dsRNA binding is required. Co-immunoprecipitation, AlphaFold structural modeling, mutagenesis, in vivo/in vitro PKR phosphorylation assays Cell reports High 39146181
2019 PKR promotes cGAS condensation and DNA sensing by an RNA-dependent association with G3BP1 to facilitate G3BP1 foci formation; loss of G3BP1 blocks cGAS condensation and suppresses interferon response to cytoplasmic DNA. Co-immunoprecipitation, knockdown, immunofluorescence, interferon response assays Science signaling Medium 31772125
2020 Structured expansion RNAs (CAG, CCUG, CAGG, G4C2) activate PKR, which promotes RAN (repeat-associated non-AUG) translation; blocking PKR with dominant-negative PKR-K296R or PKR-KO reduces RAN protein levels; metformin inhibits PKR and reduces RAN proteins and improves pathology in C9orf72 ALS/FTD mice. PKR-KO cells, dominant-negative PKR, AAV-mediated PKR inhibition in transgenic mice, RAN protein quantification Proceedings of the National Academy of Sciences of the United States of America High 32690681
2012 PKR activation in colonic epithelial cells promotes eIF2α-mediated UPR signaling, STAT3, and AKT activation to protect against DSS-induced colitis; PKR-/- mice show impaired UPR, reduced STAT3/AKT phosphorylation, and more severe colitis. PKR knockout mice, bone marrow reconstitution, western blot, histology Inflammatory bowel diseases Medium 22275310
2016 PKR kinase activity represses cryopyrin (NLRP3) inflammasome activity by inhibiting protein translation of inflammasome constituents to prevent initial priming; kinase-dead knock-in and PKR-null mice showed enhanced inflammasome activity, contradicting earlier findings that PKR promotes inflammasome activation. Knock-in mouse with kinase-dead PKR point mutation, PKR-null mouse, inflammasome activity assays Cell research High 26794869
2018 Stress-induced phosphorylation of TRBP enhances its interaction with PKR and inhibits PKR activity more efficiently, promoting cell survival by preventing sustained PKR-mediated apoptosis. Co-immunoprecipitation, TRBP phospho-mutants, PKR activity assays, cell survival assays Scientific reports Medium 29348664
2012 PKR activation during ER stress (via PACT) promotes p53 sumoylation on Lys386 through interaction with SUMO E2 ligase Ubc9; this pathway requires both PACT and PKR and leads to p53 stability, p21 induction, and G1 cell cycle arrest. Co-expression, dominant-negative PKR, PKR-null MEFs, sumoylation assays, cell cycle analysis Cell cycle Medium 22214662
2022 CircRNA-CREIT acts as a scaffold to facilitate interaction between PKR and E3 ubiquitin ligase HACE1, promoting K48-linked polyubiquitylation and proteasomal degradation of PKR protein, thereby reducing PKR/eIF2α signaling and stress granule assembly. RNA pull-down, Co-IP, ubiquitylation assays, western blot, animal models Journal of hematology & oncology Medium 36038948
2023 CircWDR37 binds to and dimerizes PKR to initiate PKR autophosphorylation; phosphorylated PKR induces IKKβ phosphorylation and releases RELA from IκBα (independent of PKR kinase activity for NF-κB activation) to stimulate NF-κB target gene transcription driving senescence. RNA pull-down, Co-IP, PKR dimerization assays, IKKβ phosphorylation, NF-κB reporter, kinase-dead mutant Advanced science Medium 36683218
2022 APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalance the PKR-suppressing activity of ADAR1 during viral infection; APOBEC3B localizes to stress granules through interaction with PABPC1 and protects mRNA in stress granules from RNase L-mediated cleavage. Co-immunoprecipitation, PKR phosphorylation assays, stress granule imaging, RNase L assays Nature communications Medium 36781883
2020 EIF2AK2/PKR is a direct binding target of berberine; berberine inhibits PKR dimerization (rather than its enzymatic activity), selectively modulating downstream JNK, NF-κB, AKT, and NLRP3 pathways; EIF2AK2 knockdown attenuates berberine's anti-inflammatory effects. Chemoproteomics (thermal shift, DARTS), isothermal titration calorimetry, PKR dimerization assay, EIF2AK2 knockdown mice Acta pharmaceutica Sinica. B Medium 37250154
2020 Heterozygous de novo missense variants in EIF2AK2 cause reduced kinase activity in patient-derived fibroblasts and mammalian cell lines, resulting in impaired eIF2α phosphorylation; this establishes EIF2AK2 kinase activity as required for normal neurodevelopment. Patient-derived fibroblasts, heterologous kinase activity assays American journal of human genetics Medium 32197074
2023 Reduction of renal tubular PNPT1 causes leakage of mitochondrial dsRNA into the cytoplasm, activating PKR and leading to eIF2α phosphorylation and translational arrest; PKR inhibition rescues renal tubular injury in ischemia-reperfusion and ureteral obstruction mouse models. PKR inhibition (pharmacological and genetic), PNPT1 knockout mice, eIF2α phosphorylation assays, mouse injury models Nature communications High 36869030

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 652 31031002
2012 Novel role of PKR in inflammasome activation and HMGB1 release. Nature 639 22801494
2010 Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic acids research 511 20457754
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
2005 Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell 301 16179259
2013 Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proceedings of the National Academy of Sciences of the United States of America 300 23898178
2012 Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Molecular cell 232 23084476
2019 PKR: A Kinase to Remember. Frontiers in molecular neuroscience 213 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 196 30174290
2000 PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Molecular and cellular biology 194 10848580
2008 Mechanism of PKR Activation by dsRNA. Journal of molecular biology 168 18599071
2022 CircRNA-CREIT inhibits stress granule assembly and overcomes doxorubicin resistance in TNBC by destabilizing PKR. Journal of hematology & oncology 148 36038948
2012 Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway. Biochimica et biophysica acta 144 22306812
1995 Regulation of the interferon-induced PKR: can viruses cope? Trends in microbiology 142 7537157
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
2014 DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation. PLoS pathogens 129 24651521
2021 RNA circles with minimized immunogenicity as potent PKR inhibitors. Molecular cell 126 34951963
2006 Activation of PKR: an open and shut case? Trends in biochemical sciences 124 17196820
2004 TRAF family proteins link PKR with NF-kappa B activation. Molecular and cellular biology 121 15121867
2014 PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator. Genes & development 119 24939934
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
2006 Molecular basis for PKR activation by PACT or dsRNA. Proceedings of the National Academy of Sciences of the United States of America 108 16785445
2008 Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nature structural & molecular biology 106 19043413
2015 Potential role for snoRNAs in PKR activation during metabolic stress. Proceedings of the National Academy of Sciences of the United States of America 97 25848059
2009 Activation of the Antiviral Kinase PKR and Viral Countermeasures. Viruses 97 21994559
2001 The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. The EMBO journal 96 11447118
2018 The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression. Molecular cell 95 29429924
2014 The impact of PKR activation: from neurodegeneration to cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 84 24522206
2012 PKR-dependent inflammatory signals. Science signaling 84 23092889
2023 ADAR1p150 prevents MDA5 and PKR activation via distinct mechanisms to avert fatal autoinflammation. Molecular cell 79 37797622
2008 PERK and PKR: old kinases learn new tricks. Cell cycle (Georgetown, Tex.) 78 18418049
2021 Inhibition of PKR by Viruses. Frontiers in microbiology 75 34759908
2009 RNA dimerization promotes PKR dimerization and activation. Journal of molecular biology 69 19445956
2010 Multiple levels of PKR inhibition during HIV-1 replication. Reviews in medical virology 64 21294215
2000 Potential role of PKR in double-stranded RNA-induced macrophage activation. The EMBO journal 64 10899117
2017 PKR involvement in Alzheimer's disease. Alzheimer's research & therapy 63 28982375
2022 Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects. Acta pharmaceutica Sinica. B 62 37250154
2013 The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication. Retrovirology 60 24020926
2020 De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. American journal of human genetics 59 32197074
2013 Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice. Diabetes 59 24150608
1994 Proteins that interact with PKR. Biochimie 57 7893827
2021 A tale of two proteins: PACT and PKR and their roles in inflammation. The FEBS journal 55 33387379
2019 PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing. Science signaling 54 31772125
2014 Activation of the PKR/eIF2α signaling cascade inhibits replication of Newcastle disease virus. Virology journal 53 24684861
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.) 50 18217692
2022 dsRNA-induced condensation of antiviral proteins modulates PKR activity. Proceedings of the National Academy of Sciences of the United States of America 49 35939694
2013 Activation of protein kinase PKR requires dimerization-induced cis-phosphorylation within the activation loop. The Journal of biological chemistry 49 24338483
2007 Conserved intermolecular salt bridge required for activation of protein kinases PKR, GCN2, and PERK. The Journal of biological chemistry 49 17202131
2010 Regulation of PKR by HCV IRES RNA: importance of domain II and NS5A. Journal of molecular biology 48 20447405
2023 Chemotherapy-Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA-Mediated PKR Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 43 36683218
2012 PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling. Inflammatory bowel diseases 43 22275310
2011 Characterization of a ranavirus inhibitor of the antiviral protein kinase PKR. BMC microbiology 42 21418572
2008 Essential role of PACT-mediated PKR activation in tunicamycin-induced apoptosis. Journal of molecular biology 42 19007793
2020 Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway. Frontiers in physiology 41 32508669
2018 Stress-induced TRBP phosphorylation enhances its interaction with PKR to regulate cellular survival. Scientific reports 41 29348664
2012 The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G₁ arrest. Cell cycle (Georgetown, Tex.) 40 22214662
2022 Viral evasion of PKR restriction by reprogramming cellular stress granules. Proceedings of the National Academy of Sciences of the United States of America 39 35858300
2017 PKR induces the expression of NLRP3 by regulating the NF-κB pathway in Porphyromonas gingivalis-infected osteoblasts. Experimental cell research 39 28341446
2010 Role of PKR and Type I IFNs in viral control during primary and secondary infection. PLoS pathogens 39 20585572
2022 YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in Oxaliplatin-Resistant Colorectal Cancer. ACS chemical biology 37 35708211
2015 PKR downregulation prevents neurodegeneration and β-amyloid production in a thiamine-deficient model. Cell death & disease 36 25590804
2022 Signaling by the integrated stress response kinase PKR is fine-tuned by dynamic clustering. The Journal of cell biology 34 35522180
2018 Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma. Biochimica et biophysica acta. Molecular basis of disease 34 29486283
2015 Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors. Molecular medicine (Cambridge, Mass.) 34 26052716
2023 APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection. Nature communications 33 36781883
2016 The kinase activity of PKR represses inflammasome activity. Cell research 33 26794869
2018 ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication. Cytokine & growth factor reviews 32 29625900
2016 IRE1α mediates PKR activation in response to Chlamydia trachomatis infection. Microbes and infection 31 27021640
2016 nc886, a non-coding RNA and suppressor of PKR, exerts an oncogenic function in thyroid cancer. Oncotarget 31 27612419
2013 PKR regulates proliferation, differentiation, and survival of murine hematopoietic stem/progenitor cells. Blood 31 23403623
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 29 32539931
2011 Heparin activates PKR by inducing dimerization. Journal of molecular biology 29 21978664
2009 Biochemical analysis of PKR activation by PACT. Biochemistry 29 19580324
1998 RNA binding and modulation of PKR activity. Methods (San Diego, Calif.) 29 9735304
2018 Novel role of PKR in palmitate-induced Sirt1 inactivation and endothelial cell senescence. American journal of physiology. Heart and circulatory physiology 28 29906232
2021 EIF2AK2 selectively regulates the gene transcription in immune response and histones associated with systemic lupus erythematosus. Molecular immunology 27 33588244
2000 A new double-stranded RNA-binding protein that interacts with PKR. Nucleic acids research 27 10684936
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
2023 Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis. Nature communications 25 36869030
2014 HIV-1 translation and its regulation by cellular factors PKR and PACT. Virus research 25 25064266
2013 Inhibition of PKR protects against tunicamycin-induced apoptosis in neuroblastoma cells. Gene 25 24334130
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
2016 Enterovirus 71 induces dsRNA/PKR-dependent cytoplasmic redistribution of GRP78/BiP to promote viral replication. Emerging microbes & infections 24 27004760
2016 The Specific Protein Kinase R (PKR) Inhibitor C16 Protects Neonatal Hypoxia-Ischemia Brain Damages by Inhibiting Neuroinflammation in a Neonatal Rat Model. Medical science monitor : international medical journal of experimental and clinical research 24 28008894
2015 Regulation of PKR by RNA: formation of active and inactive dimers. Biochemistry 24 26488609
2020 eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition. mBio 23 32665273
2018 The Noncoding RNA nc886 Regulates PKR Signaling and Cytokine Production in Human Cells. Journal of immunology (Baltimore, Md. : 1950) 23 30518569
2017 Interaction of PKR with single-stranded RNA. Scientific reports 23 28611419
2013 Double-stranded RNA binding by the human cytomegalovirus PKR antagonist TRS1. Virology 23 23601785
2024 EIF2AK2 protein targeted activation of AIM2-mediated PANoptosis promotes sepsis-induced acute kidney injury. Renal failure 22 39311631
2016 Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition. Biomarkers in cancer 22 27486347
2024 An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation. Cell reports 21 39146181