{"gene":"EIF2AK3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1998,"finding":"PEK (EIF2AK3/PERK) is a new eIF-2α kinase that autophosphorylates on serine and threonine residues and specifically phosphorylates eIF-2α on serine-51 in vitro; addition of recombinant PEK to reticulocyte lysates causes dose-dependent inhibition of translation, and PEK functionally substitutes for yeast GCN2 in a process requiring eIF-2α Ser-51.","method":"Recombinant protein produced in E. coli and Sf-9 insect cells; in vitro kinase assay; reticulocyte lysate translation assay; yeast complementation with eIF-2α Ser-51 mutant","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro kinase activity with substrate specificity, mutagenesis (Ser-51), functional rescue in yeast, and translation inhibition assay; multiple orthogonal methods in founding paper","pmids":["9819435"],"is_preprint":false},{"year":1999,"finding":"A catalytic-dead point mutant of PEK (Lys-614→Ala) abolishes eIF-2α kinase activity but retains autophosphorylation when expressed in Sf-9 cells, demonstrating that autophosphorylation and substrate phosphorylation are mechanistically separable. PEK protein co-localizes with somatostatin in pancreatic delta cells.","method":"Site-directed mutagenesis; kinase assay in Sf-9 cells; immunohistochemistry co-localization with somatostatin","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with in vitro kinase assay; single lab, two complementary methods","pmids":["10026192"],"is_preprint":false},{"year":2000,"finding":"The N-terminal luminal domain of PERK/PEK is required for its activation by ER stress; deletion of these N-terminal sequences abolishes elevated PEK autophosphorylation and eIF-2α kinase activity during ER stress in mammalian cells.","method":"Deletion mutagenesis of N-terminal luminal sequences; eIF-2α kinase activity assay in mammalian cells under ER stress","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — domain-deletion mutagenesis with functional kinase assay; single lab, two orthogonal methods","pmids":["10677345"],"is_preprint":false},{"year":2000,"finding":"PERK activation during the UPR signals loss of cyclin D1 by increasing eIF-2α phosphorylation, thereby blocking cyclin D1 translation and causing G1-phase cell-cycle arrest. A truncated kinase-dead dominant-negative PERK attenuates cyclin D1 loss and cell-cycle arrest without compromising ER chaperone induction.","method":"Overexpression of wild-type and dominant-negative PERK; immunoblot for cyclin D1 and p-eIF2α; cell-cycle analysis by flow cytometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative genetics plus gain-of-function overexpression, reciprocal effects confirmed, specific mechanistic pathway (eIF2α→cyclin D1 translation) established","pmids":["11035797"],"is_preprint":false},{"year":2000,"finding":"Loss-of-function mutations in EIF2AK3 (truncation removing the catalytic domain, and a missense mutation in the catalytic domain) segregate with Wolcott-Rallison syndrome, establishing that EIF2AK3 kinase activity is required for normal pancreatic beta-cell function and prevention of neonatal diabetes.","method":"Genetic mapping; sequencing of EIF2AK3 in affected families; functional inference from catalytic-domain truncation/missense","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics with loss-of-function alleles directly abolishing the catalytic domain; replicated across multiple families","pmids":["10932183"],"is_preprint":false},{"year":2004,"finding":"Missense mutations in EIF2AK3 associated with Wolcott-Rallison syndrome produce proteins with complete loss of kinase activity (four mutants) or residual kinase activity (one mutant), as measured in vivo and in vitro; residual activity correlates with later onset of diabetes.","method":"In vitro and in vivo kinase activity assays of missense EIF2AK3 mutants; genotype-phenotype correlation","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay of disease-associated mutants; multiple mutants tested; genotype-phenotype correlation across multiple families","pmids":["15220213"],"is_preprint":false},{"year":2006,"finding":"PERK is specifically required in insulin-secreting beta cells during fetal and early neonatal development for beta-cell proliferation, differentiation, and proinsulin trafficking; PERK expression in adult beta cells is not required to maintain glucose homeostasis, established by tissue-specific conditional knockout.","method":"Tissue- and cell-specific Perk conditional knockout mice; developmental analysis of beta-cell mass, proinsulin trafficking, and insulin secretion","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with defined cellular phenotypes; multiple independent conditional lines tested","pmids":["17141632"],"is_preprint":false},{"year":2010,"finding":"Loss of PERK function impairs ER-to-Golgi anterograde trafficking of proinsulin, retrotranslocation from the ER, and proteasomal degradation (ERAD); PERK is a positive regulator of ERAD and proteasomal activity in beta cells.","method":"Cell culture and mouse models with Perk impairment or gene-dosage modulation; proinsulin trafficking assays; proteasomal degradation assays; Ins2 Akita mouse epistasis","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (KO, hypomorph, haploinsufficiency) with defined trafficking and degradation readouts; replicated in vivo and in vitro","pmids":["20530744"],"is_preprint":false},{"year":2010,"finding":"PERK deficiency in mammary tumor cells impairs regeneration of intracellular antioxidants, causes accumulation of reactive oxygen species, and triggers oxidative DNA damage and DNA damage checkpoint activation, thereby impeding cell-cycle progression and tumor growth.","method":"Perk knockout in tumor cells; ROS measurement; DNA damage markers; cell-cycle analysis; animal mammary carcinoma model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation with specific ROS and DNA-damage readouts in vitro and in vivo; single lab, multiple methods","pmids":["20453876"],"is_preprint":false},{"year":2013,"finding":"GSK2656157 is an ATP-competitive PERK kinase inhibitor (IC50 0.9 nM) that inhibits PERK autophosphorylation, eIF2α substrate phosphorylation, and downstream ATF4/CHOP induction in cells; oral dosing produces pharmacodynamic inhibition of PERK autophosphorylation in mouse pancreas.","method":"Biochemical ATP-competitive kinase assay; cellular phosphorylation assays; kinase selectivity panel (300 kinases); in vivo pharmacodynamic studies in mice","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous biochemical characterization including selectivity panel, cellular substrate phosphorylation, and in vivo PD; multiple orthogonal methods","pmids":["23333938"],"is_preprint":false},{"year":2016,"finding":"PERK inhibits DNA replication during ER stress by promoting phosphorylation of the checkpoint adaptor Claspin and activation of Chk1 kinase, leading to replication fork slowing and reduced origin firing, independently of detectable DNA damage; Claspin depletion or Chk1 inhibition abolishes PERK-dependent DNA synthesis inhibition.","method":"PERK-dependent thapsigargin treatment; DNA synthesis assays; Claspin and Chk1 depletion/inhibition; replication origin firing analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic depletion of pathway components (PERK, Claspin, Chk1) with specific replication readouts; epistasis established across multiple orthogonal methods","pmids":["27375025"],"is_preprint":false},{"year":2017,"finding":"PERK promotes degradation of cyclin D1 and p53 via the 26S proteasome during ER stress, representing a non-translational function of PERK in regulating protein stability.","method":"Overexpression/loss-of-function of PERK during ER stress; proteasome inhibitor experiments; protein stability assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — described as a demonstrated finding with pharmacological and genetic tools; single lab, limited methodological detail in abstract","pmids":["18418049"],"is_preprint":false},{"year":2017,"finding":"PERK induces expression of miR-211 upon UPR activation; miR-211 directly suppresses Bmal1 and Clock to produce a 10-hour phase shift in circadian oscillations, and repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation.","method":"miRNA profiling; miR-211 target validation; luciferase reporter assays; PERK genetic manipulation; protein synthesis assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PERK genetic manipulation linked to miR-211 induction and direct circadian regulator suppression; single lab with multiple orthogonal methods","pmids":["29230015"],"is_preprint":false},{"year":2017,"finding":"CNPY2 (canopy homolog 2) is released from GRP78 upon ER stress and engages PERK to induce CHOP expression, initiating the UPR; CNPY2 deletion blocks the PERK-CHOP pathway in vivo.","method":"Co-immunoprecipitation of CNPY2 with PERK; CNPY2 knockout mice; CHOP pathway reporter assays; liver damage model","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP binding, in vivo genetic deletion, and functional pathway reporter; multiple orthogonal methods with in vivo validation","pmids":["28869608"],"is_preprint":false},{"year":2017,"finding":"PERK drives cancer invasion and metastasis through the transcription factor CREB3L1, which acts downstream of PERK specifically in mesenchymal triple-negative breast cancer cells; inhibition of CREB3L1 suppresses PERK-dependent invasion.","method":"PERK and CREB3L1 genetic manipulation; invasion and metastasis assays in vitro and in vivo; epistasis placing CREB3L1 downstream of PERK","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in cell and animal models; single lab, multiple experimental approaches","pmids":["29057869"],"is_preprint":false},{"year":2017,"finding":"DLK (Dual Leucine Zipper Kinase) activates PERK signaling in neurons in response to nerve injury and neurotrophin deprivation, leading to ATF4 upregulation via the ISR; disruption of PERK signaling delays neurodegeneration without reducing JNK signaling, placing PERK downstream of DLK in a neuronal stress pathway.","method":"Mouse nerve injury models; DLK and PERK genetic manipulation; ATF4 measurement; JNK and PERK pathway epistasis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple injury models and pathway dissection; single lab, multiple complementary approaches","pmids":["28440222"],"is_preprint":false},{"year":2018,"finding":"PERK regulates proinsulin proteostasis not by controlling synthesis rates (global protein and proinsulin synthesis are both down-regulated in PERK-inhibited cells) but by modulating ER chaperones BiP and ERp72; ERp72 overexpression rescues proinsulin aggregation whereas BiP manipulation promotes it.","method":"PERK inhibition in cell culture and mice; high-resolution imaging; protein fractionation; immunological assays; BiP and ERp72 overexpression/knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, fractionation, genetic rescue/knockdown) in multiple model systems; definitively negates a prior hypothesis and establishes chaperone regulation as mechanism","pmids":["29444822"],"is_preprint":false},{"year":2019,"finding":"BiP interaction with the luminal domains of PERK (and IRE1) switches BiP from its chaperone ATPase cycle into an ER stress sensor cycle by preventing co-chaperone binding and loss of ATPase stimulation; misfolded protein-dependent dissociation of BiP from PERK/IRE1 is primed by ATP but not ADP.","method":"Reconstitution of human UPR components in vitro; biochemical co-chaperone binding assays; ATPase stimulation assays; nucleotide (ATP vs ADP) dependence experiments","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of human components with mechanistic nucleotide and co-chaperone competition assays; multiple orthogonal biochemical methods","pmids":["31695187"],"is_preprint":false},{"year":2019,"finding":"TMAO (trimethylamine N-oxide) directly binds to PERK at physiologically relevant concentrations and selectively activates the PERK branch of the UPR, inducing FoxO1 in a PERK-dependent manner; interventions reducing TMAO reduce PERK activation and FoxO1 levels in liver.","method":"Direct TMAO-PERK binding assay; selective UPR branch activation assays; PERK-dependent FoxO1 induction; gut microbiota manipulation and FMO3 inhibition experiments in vivo","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding demonstrated plus functional selectivity assays and in vivo epistasis; single lab with multiple orthogonal approaches","pmids":["31543404"],"is_preprint":false},{"year":2019,"finding":"PERK activation during ER stress and glucose deprivation stimulates formation of respiratory chain supercomplexes (SCs) through the PERK-eIF2α-ATF4 axis, which increases SCAF1 (COX7A2L) expression; PERK ablation suppresses SC levels and oxidative phosphorylation-dependent ATP production.","method":"Genetic ablation and pharmacological inhibition of PERK; measurement of SC levels; SCAF1 expression; OXPHOS ATP production; PERK activation in mitochondrial disease patient cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological PERK manipulation with mechanistic downstream pathway (ATF4→SCAF1→SCs) established; multiple model systems","pmids":["31023583"],"is_preprint":false},{"year":2019,"finding":"PERK-dependent translational inhibition extends beyond global translation to specifically repress ER-targeted proteins (transmembrane, glycoproteins, disulfide-bond-containing) via ribosome footprint profiling; PERK also attenuates expression of a subset of XBP1-ATF6 UPR targets, demonstrating cross-talk between UPR branches.","method":"Ribosome footprint profiling (Ribo-seq) in WT vs PERK-/- mouse embryonic fibroblasts; RNA-seq; ER stress time-course experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome footprint profiling in genetic null cells with global and selective repression analysis; single lab, genome-wide method","pmids":["30867432"],"is_preprint":false},{"year":2021,"finding":"Thrombospondin-1 (Thbs1) directly binds and activates PERK, inducing its downstream transcription factor ATF4 and causing autophagy-mediated lethal cardiac atrophy; genetic deletion of PERK in Thbs1 transgenic mice blunts ATF4 induction, autophagy, and cardiac atrophy.","method":"Co-immunoprecipitation of Thbs1 and PERK; Thbs1 transgenic mice; Perk cardiac-specific knockout; ATF4 and autophagy marker measurement; AAV9 gene transfer of PERK and ATF4","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP binding plus genetic ablation (PERK KO rescues lethal phenotype) and gain-of-function (AAV9-PERK reproduces atrophy); multiple orthogonal methods in vivo","pmids":["34168130"],"is_preprint":false},{"year":2022,"finding":"The oxidoreductase ERO1α covalently interacts with PERK upon ER stress (tunicamycin treatment), requiring the C-terminal active site of ERO1α and cysteine 216 of PERK; the PERK-ERO1α complex promotes oxidization of mitochondria-ER contact (MERC) proteins, controls mitochondrial dynamics, and improves ER-mitochondria Ca2+ flux to maintain bioenergetics.","method":"Co-immunoprecipitation; cysteine mutagenesis (C216 of PERK); proteinaceous Ca2+ probes at MERC; mitochondrial dynamics imaging; bioenergetic assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — covalent interaction identified with site-specific mutagenesis (C216), functional consequences on MERC and Ca2+ flux measured with orthogonal methods; single lab, multiple rigorous approaches","pmids":["36586409"],"is_preprint":false},{"year":2022,"finding":"PERK mediates immunosuppressive M2 macrophage activation and proliferation downstream of IL-4 and tumor microenvironment signals, acting through the PERK-ATF4 axis to upregulate PSAT1 (phosphoserine aminotransferase 1) and serine biosynthesis; increased serine leads to enhanced α-ketoglutarate production required for JMJD3-dependent epigenetic modification.","method":"PERK knockout/inhibition in macrophages; metabolomics; ATF4 and PSAT1 genetic manipulation; α-ketoglutarate and JMJD3 assays; in vivo tumor models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with metabolomic and epigenetic pathway dissection; multiple orthogonal methods and in vivo validation","pmids":["35228694"],"is_preprint":false},{"year":2022,"finding":"PERK in hematopoietic stem/progenitor cells (HSPCs) in the spleen reprograms HSPCs into committed MDSC precursors via PERK-ATF4-C/EBPβ signaling; pharmacological or genetic PERK inhibition in HSPCs prevents myeloid descendants from becoming MDSCs.","method":"Genetic and pharmacological PERK inhibition in murine and human HSPCs; spleen-targeted PERK antagonist delivery; tumor models; MDSC functional assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological manipulation in multiple in vitro and in vivo models; pathway dissection via ATF4-C/EBPβ; single lab","pmids":["35266960"],"is_preprint":false},{"year":2023,"finding":"PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) during acute ER stress, requiring YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1; accumulated outer-mitochondrial-membrane PA inhibits mitochondrial fission and induces protective mitochondrial elongation.","method":"PERK genetic ablation and activation; PA lipid measurements; YME1L and PRELID1 genetic manipulation; mitochondrial morphology imaging; fission assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (PERK→YME1L→PRELID1→PA→elongation) with lipid measurements and morphology readouts; multiple orthogonal methods","pmids":["37306086"],"is_preprint":false},{"year":2024,"finding":"ATAD3A (mitochondrial ATPase AAA domain-containing protein 3A) interacts with PERK and competes for binding with PERK's target eIF2, forming mitochondria-ER contact sites; during ER stress PERK-ATAD3A interactions increase, attenuating local PERK signaling at mitochondria and protecting active translation there from ER stress-induced repression.","method":"Live-cell imaging of reporter mRNA translation; Co-immunoprecipitation of PERK-ATAD3A; competition binding assay with eIF2; ATAD3A knockdown; PERK-ATAD3A proximity ligation at mitochondria-ER contacts","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — live-cell translation imaging, Co-IP, competition binding, and localization at MERCs; multiple orthogonal methods in single rigorous study","pmids":["39116259"],"is_preprint":false},{"year":2024,"finding":"TRIM29 interacts with PERK and promotes SUMOylation of PERK to maintain its protein stability, thereby sustaining PERK-mediated signaling pathways in cardiomyocytes during viral infection; TRIM29 loss reduces PERK stability and PERK-mediated ER stress responses.","method":"Co-immunoprecipitation of TRIM29 and PERK; SUMOylation assays; TRIM29 knockout mice; viral myocarditis model; PERK stability assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding, post-translational modification (SUMOylation) identified, in vivo genetic model; single lab, multiple methods","pmids":["38664417"],"is_preprint":false},{"year":2016,"finding":"miR-204 directly targets the 3′UTR of PERK mRNA and reduces PERK protein expression and downstream ATF4/CHOP signaling in beta cells; miR-204-mediated PERK inhibition exacerbates ER stress-induced beta-cell apoptosis.","method":"3′UTR luciferase reporter assay; miR-204 overexpression in primary human islets, mouse islets, and INS-1 cells; immunoblot for PERK and downstream targets; cell death assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3′UTR targeting validated by reporter assay, confirmed in primary human tissue; single lab, multiple cell types","pmids":["27384111"],"is_preprint":false},{"year":2019,"finding":"FOXO3 directly binds the PERK promoter and transcriptionally activates PERK expression, as confirmed by ChIP, siRNA knockdown, overexpression assays, and Foxo1/3/4-/- MEFs; PERK is thus a direct transcriptional downstream target of FOXO3.","method":"ChIP; siRNA knockdown; FOXO3 overexpression; Foxo1/3/4 triple-knockout MEFs; RT-qPCR and immunoblot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding; validated in genetic null cells; single lab, multiple orthogonal methods","pmids":["31312024"],"is_preprint":false},{"year":2019,"finding":"JEV non-structural protein NS4B binds PERK via its LIG-FHA and LIG-WD40 domains (both required), inducing PERK dimerization, which is the mechanistic basis of JEV-induced PERK activation leading to the PERK-ATF4-CHOP apoptosis pathway.","method":"Co-immunoprecipitation of NS4B with PERK; glycerol gradient centrifugation for PERK dimerization; domain-deletion mutagenesis of NS4B; PERK inhibitor experiments in vitro and in vivo","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding with domain mapping and dimerization assay; single lab with complementary methods","pmids":["31189710"],"is_preprint":false},{"year":2019,"finding":"PTH induces ER stress in osteoblasts through the PERK-eIF2α-ATF4 signaling pathway; HSP90 interacts with PERK and maintains PERK protein stabilization early during PTH-induced ER stress; HSP90 inhibition decreases PERK protein expression and inhibits osteoblast differentiation and proliferation upon PTH treatment.","method":"PERK/ATF4 siRNA and pharmacological inhibitors; co-immunoprecipitation of HSP90 with PERK; geldanamycin (HSP90 inhibitor) treatment; osteoblast differentiation and proliferation assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies HSP90-PERK interaction; functional consequences confirmed by HSP90 inhibitor; single lab, multiple methods","pmids":["30668150"],"is_preprint":false},{"year":2022,"finding":"Mfn2 physically interacts with PERK at mitochondria-associated ER membranes (MAMs); high glucose promotes a decrease in the Mfn2-PERK interaction; Mfn2 silencing activates the PERK pathway and increases podocyte apoptosis, while PERK inhibition protects mitochondrial function without affecting Mfn2 expression, placing PERK downstream of Mfn2 at MAMs.","method":"Co-immunoprecipitation of Mfn2 and PERK; Mfn2 siRNA knockdown; PERK inhibitor treatment; MAM ultrastructure analysis; mitochondrial function assays in podocytes","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding with genetic epistasis (Mfn2→PERK) established by knockdown and inhibitor; single lab, multiple methods","pmids":["34988075"],"is_preprint":false}],"current_model":"EIF2AK3/PERK is an ER-resident transmembrane serine/threonine kinase that autophosphorylates and phosphorylates eIF-2α on Ser-51 to inhibit global translation during ER stress; its luminal domain senses unfolded proteins (switching BiP from chaperone to sensor mode), and upon activation it signals through eIF2α-ATF4-CHOP to orchestrate translational repression, cell-cycle arrest (via cyclin D1 loss), mitochondrial bioenergetics (respiratory supercomplex assembly, PA remodeling for elongation, PERK-ERO1α covalent complex for Ca2+ flux), and selective autophagy regulation, while its activity is regulated by binding partners including BiP, Thbs1, CNPY2, HSP90, ATAD3A, Mfn2, ERO1α, and TRIM29 (which SUMOylates PERK to stabilize it), with loss-of-function mutations causing Wolcott-Rallison syndrome through impaired beta-cell proliferation, differentiation, and ER chaperone-dependent proinsulin quality control."},"narrative":{"mechanistic_narrative":"EIF2AK3 (PERK) is an ER-resident eIF-2α kinase that couples sensing of ER stress to translational and transcriptional reprogramming of the cell. It autophosphorylates on serine/threonine residues and specifically phosphorylates eIF-2α on Ser-51 to inhibit translation, with autophosphorylation and substrate phosphorylation being mechanistically separable functions [PMID:9819435, PMID:10026192]. Its N-terminal luminal domain is required for activation during ER stress [PMID:10677345], a step gated by BiP, which switches from its chaperone ATPase cycle into a stress-sensor cycle through interaction with the PERK luminal domain and dissociates from PERK upon accumulation of misfolded proteins [PMID:31695187]. Activated PERK signals predominantly through the eIF2α-ATF4 axis to drive diverse outcomes: G1 cell-cycle arrest via loss of cyclin D1 translation [PMID:11035797], replication-fork slowing through Claspin/Chk1 [PMID:27375025], redox and antioxidant homeostasis [PMID:20453876], and a broad mitochondrial program including respiratory supercomplex assembly via ATF4-SCAF1 [PMID:31023583], adaptive phosphatidic-acid remodeling driving protective mitochondrial elongation [PMID:37306086], and a covalent PERK-ERO1α complex at mitochondria-ER contacts that controls Ca2+ flux and bioenergetics [PMID:36586409]. In pancreatic beta cells PERK is required during fetal and neonatal development for proliferation, differentiation, and proinsulin proteostasis, the latter mediated through control of ER chaperones BiP and ERp72 and through positive regulation of ERAD rather than synthesis rate [PMID:17141632, PMID:20530744, PMID:29444822]. Loss-of-function mutations in EIF2AK3 that abolish or reduce kinase activity cause Wolcott-Rallison syndrome, with residual activity correlating with later-onset neonatal diabetes [PMID:10932183, PMID:15220213]. PERK activity is tuned by an array of binding partners and upstream activators, including CNPY2, Thbs1, the viral protein NS4B, and the metabolite TMAO that act as activators [PMID:28869608, PMID:34168130, PMID:31189710, PMID:31543404], and by HSP90, TRIM29, ATAD3A, and Mfn2 that regulate its stability, localization, and local signaling [PMID:30668150, PMID:38664417, PMID:39116259, PMID:34988075].","teleology":[{"year":1998,"claim":"Establishing that PERK is a bona fide eIF-2α kinase defined the molecular activity that anchors all downstream biology.","evidence":"Recombinant kinase produced in E. coli/Sf-9, in vitro kinase assay with Ser-51 specificity, reticulocyte translation assay, and yeast GCN2 complementation","pmids":["9819435"],"confidence":"High","gaps":["Did not address how the kinase is activated in cells","No structural basis for substrate recognition"]},{"year":1999,"claim":"Separating autophosphorylation from substrate phosphorylation and localizing PERK to pancreatic delta cells clarified its catalytic logic and tissue distribution.","evidence":"Lys-614→Ala active-site mutant in Sf-9 cells; immunohistochemical co-localization with somatostatin","pmids":["10026192"],"confidence":"Medium","gaps":["Delta-cell co-localization did not establish a delta-cell function","Mechanism linking autophosphorylation to substrate phosphorylation unresolved"]},{"year":2000,"claim":"Defining the luminal domain as the ER-stress activation module placed PERK as a transmembrane stress sensor.","evidence":"Deletion of N-terminal luminal sequences abolishing stress-induced autophosphorylation and kinase activity in mammalian cells","pmids":["10677345"],"confidence":"Medium","gaps":["Did not identify the luminal ligand or sensing mechanism","Single domain-deletion approach"]},{"year":2000,"claim":"Linking PERK to cyclin D1 loss and G1 arrest, and to Wolcott-Rallison syndrome, connected the kinase to cell-cycle control and human disease.","evidence":"Dominant-negative/overexpression PERK with cyclin D1 immunoblot and flow cytometry; genetic mapping and sequencing of EIF2AK3 in WRS families","pmids":["11035797","10932183"],"confidence":"High","gaps":["Disease mapping inferred kinase requirement without functional assay of all alleles","Cell-cycle mechanism shown in overexpression context"]},{"year":2004,"claim":"Functionally testing WRS-associated missense alleles established kinase activity as the disease-relevant output and produced a genotype-phenotype dose relationship.","evidence":"In vitro and in vivo kinase assays of five missense mutants with genotype-phenotype correlation","pmids":["15220213"],"confidence":"High","gaps":["Did not resolve the beta-cell-specific cellular defect","Residual-activity threshold for disease onset not defined mechanistically"]},{"year":2006,"claim":"Conditional knockout showed PERK acts developmentally in beta cells, dissociating its requirement in fetal/neonatal beta-cell biology from adult glucose homeostasis.","evidence":"Tissue- and cell-specific Perk conditional knockout mice with beta-cell mass, proinsulin trafficking, and secretion analysis","pmids":["17141632"],"confidence":"High","gaps":["Molecular mechanism of trafficking defect not yet defined","Why adult beta cells tolerate PERK loss unexplained"]},{"year":2010,"claim":"Two studies extended PERK function to ERAD/proteasomal trafficking in beta cells and to antioxidant/ROS control in tumor cells, broadening its proteostatic and redox roles.","evidence":"Perk genetic models with proinsulin trafficking and ERAD assays (Ins2 Akita epistasis); Perk knockout tumor cells with ROS, DNA-damage, and cell-cycle readouts","pmids":["20530744","20453876"],"confidence":"High","gaps":["Direct PERK substrate(s) in ERAD regulation unidentified","How translational control produces antioxidant regeneration not mechanistically dissected"]},{"year":2013,"claim":"Development of a selective ATP-competitive inhibitor provided a pharmacological tool validating PERK catalytic output in cells and in vivo.","evidence":"GSK2656157 biochemical assay (IC50 0.9 nM), 300-kinase selectivity panel, cellular phosphorylation, and mouse pharmacodynamics","pmids":["23333938"],"confidence":"High","gaps":["Off-target effects in chronic settings not addressed","Does not distinguish translational from non-translational PERK functions"]},{"year":2016,"claim":"PERK was shown to enforce a replication checkpoint via Claspin/Chk1 and to be negatively regulated by miR-204, refining its cell-cycle and expression control.","evidence":"Thapsigargin-induced PERK signaling with Claspin/Chk1 depletion and replication assays; miR-204 3′UTR luciferase reporter in human/mouse islets and INS-1 cells","pmids":["27375025","27384111"],"confidence":"High","gaps":["How PERK promotes Claspin phosphorylation mechanistically unclear","Physiological signals controlling miR-204 in vivo not defined"]},{"year":2017,"claim":"Multiple studies expanded the PERK interactome and downstream effectors, identifying CNPY2 as an activator and CREB3L1, miR-211, and proteasomal cyclin D1/p53 degradation as outputs in stress, circadian, and cancer contexts.","evidence":"Co-IP and CNPY2 knockout mice; PERK genetic manipulation with CREB3L1 invasion assays, miR-211/Bmal1-Clock reporter assays, and proteasome stability assays","pmids":["28869608","29057869","29230015","18418049"],"confidence":"Medium","gaps":["Whether these branches are cell-type specific or general unresolved","Direct biochemical link from PERK to each effector incomplete"]},{"year":2017,"claim":"Identifying DLK as a neuronal upstream activator of PERK placed the kinase in an injury-responsive integrated stress pathway.","evidence":"Mouse nerve-injury models with DLK/PERK genetic manipulation, ATF4 measurement, and JNK/PERK epistasis","pmids":["28440222"],"confidence":"Medium","gaps":["Molecular mechanism by which DLK activates PERK not defined","Single neuronal injury context"]},{"year":2018,"claim":"Mechanistic dissection in beta cells showed PERK controls proinsulin proteostasis through ER chaperones rather than synthesis rate, refuting a synthesis-control model.","evidence":"PERK inhibition in cells/mice with imaging, fractionation, and BiP/ERp72 overexpression-knockdown rescue","pmids":["29444822"],"confidence":"High","gaps":["How PERK signaling modulates ERp72/BiP levels unresolved","Whether the same logic applies outside beta cells unknown"]},{"year":2019,"claim":"A cluster of studies reconstituted BiP-mediated luminal sensing, identified TMAO as a direct activating ligand, FOXO3 as a transcriptional inducer, JEV NS4B as a dimerization-driving viral activator, and HSP90 as a stabilizing partner, defining how PERK is switched on and maintained.","evidence":"In vitro reconstitution of BiP/PERK ATPase and co-chaperone competition; TMAO binding and PERK-dependent FoxO1 assays; FOXO3 ChIP and triple-KO MEFs; NS4B Co-IP/domain mapping and glycerol-gradient dimerization; HSP90 Co-IP with geldanamycin","pmids":["31695187","31543404","31312024","31189710","30668150"],"confidence":"High","gaps":["Whether BiP, ligand, and partner inputs are integrated or independent unresolved","Structural details of dimerization-driven activation incomplete"]},{"year":2019,"claim":"Genome-wide and mitochondrial studies showed PERK selectively represses ER-targeted protein translation and drives respiratory supercomplex assembly, expanding its role beyond global translational shutdown into mitochondrial bioenergetics.","evidence":"Ribo-seq/RNA-seq in WT vs PERK-/- MEFs; PERK ablation/inhibition with supercomplex, SCAF1, and OXPHOS ATP measurements","pmids":["30867432","31023583"],"confidence":"High","gaps":["How selectivity for ER-targeted transcripts is achieved unclear","Direct vs indirect control of SCAF1 by ATF4 not fully resolved"]},{"year":2021,"claim":"Thbs1 was identified as a direct PERK activator driving lethal autophagy-mediated cardiac atrophy, extending PERK's ligand-activated biology to the heart.","evidence":"Thbs1-PERK Co-IP, Thbs1 transgenic and cardiac-specific Perk knockout mice, and AAV9-PERK/ATF4 gene transfer","pmids":["34168130"],"confidence":"High","gaps":["Biochemical nature of Thbs1-PERK binding not structurally defined","How a secreted matricellular protein engages an ER-luminal sensor unresolved"]},{"year":2022,"claim":"Studies in immune cells and mitochondria established PERK-ATF4 metabolic-epigenetic reprogramming in macrophages and MDSC precursors and a covalent PERK-ERO1α complex controlling MERC Ca2+ flux.","evidence":"PERK KO/inhibition in macrophages and HSPCs with metabolomics, PSAT1/ATF4/C-EBPβ dissection, tumor models; ERO1α-PERK Co-IP with C216 mutagenesis and MERC Ca2+ probes","pmids":["35228694","35266960","36586409"],"confidence":"High","gaps":["Whether immune and mitochondrial branches share regulatory inputs unknown","How covalent ERO1α-PERK linkage forms in vivo not fully characterized"]},{"year":2022,"claim":"Mfn2 was identified as a MAM-localized partner placing PERK downstream of mitochondrial dynamics control in podocyte injury.","evidence":"Mfn2-PERK Co-IP, Mfn2 siRNA, PERK inhibition, and MAM ultrastructure/mitochondrial function assays in podocytes","pmids":["34988075"],"confidence":"Medium","gaps":["Whether Mfn2 directly suppresses PERK or via tethering unclear","Single cell-type context"]},{"year":2023,"claim":"PERK was shown to remodel mitochondrial phosphatidic acid via YME1L-PRELID1 to drive protective mitochondrial elongation, defining a lipid-based mitochondrial adaptation.","evidence":"PERK ablation/activation with PA measurements, YME1L/PRELID1 manipulation, and mitochondrial morphology/fission assays","pmids":["37306086"],"confidence":"High","gaps":["How PERK signaling controls YME1L activity unresolved","Whether this axis operates in beta cells or disease unknown"]},{"year":2024,"claim":"ATAD3A and TRIM29 were identified as regulators that locally attenuate PERK signaling at MERCs and stabilize PERK by SUMOylation, respectively, revealing spatial and post-translational control of the kinase.","evidence":"ATAD3A-PERK Co-IP, eIF2 competition binding, live-cell translation imaging, and MERC proximity ligation; TRIM29-PERK Co-IP, SUMOylation assays, and TRIM29 knockout viral myocarditis mice","pmids":["39116259","38664417"],"confidence":"High","gaps":["How ATAD3A competition is dynamically regulated during stress unclear","SUMO acceptor sites on PERK not mapped"]},{"year":null,"claim":"How the many luminal activators, cytosolic stabilizers, and spatial regulators are integrated to set PERK signaling thresholds across tissues, and the structural basis of luminal sensing, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified structural model of luminal-domain activation","Tissue-specific selection among ATF4-dependent output branches undefined","Relative contribution of translational vs non-translational PERK functions in vivo unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,5,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,17,18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,16,17]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[22,25,26,32]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,2,13,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,16,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,23,25]}],"complexes":["PERK-ERO1α covalent complex","mitochondria-ER contact sites (MERC/MAM)"],"partners":["BIP","CNPY2","THBS1","ERO1Α","ATAD3A","HSP90","MFN2","TRIM29"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZJ5","full_name":"Eukaryotic translation initiation factor 2-alpha kinase 3","aliases":["PRKR-like endoplasmic reticulum kinase","Pancreatic eIF2-alpha kinase","HsPEK","Protein tyrosine kinase EIF2AK3"],"length_aa":1116,"mass_kda":125.2,"function":"Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR) (PubMed:10026192, PubMed:10677345, PubMed:11907036, PubMed:12086964, PubMed:25925385, PubMed:31023583). Key effector of the integrated stress response (ISR) to unfolded proteins: EIF2AK3/PERK specifically recognizes and binds misfolded proteins, leading to its activation and EIF2S1/eIF-2-alpha phosphorylation (PubMed:10677345, PubMed:27917829, PubMed:31023583). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:10026192, PubMed:10677345, PubMed:31023583, PubMed:33384352). The EIF2AK3/PERK-mediated unfolded protein response increases mitochondrial oxidative phosphorylation by promoting ATF4-mediated expression of COX7A2L/SCAF1, thereby increasing formation of respiratory chain supercomplexes (PubMed:31023583). In contrast to most subcellular compartments, mitochondria are protected from the EIF2AK3/PERK-mediated unfolded protein response due to EIF2AK3/PERK inhibition by ATAD3A at mitochondria-endoplasmic reticulum contact sites (PubMed:39116259). In addition to EIF2S1/eIF-2-alpha, also phosphorylates NFE2L2/NRF2 in response to stress, promoting release of NFE2L2/NRF2 from the BCR(KEAP1) complex, leading to nuclear accumulation and activation of NFE2L2/NRF2 (By similarity). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). Involved in control of mitochondrial morphology and function (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZJ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF2AK3","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DAD1","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"STT3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF2AK3","total_profiled":1310},"omim":[{"mim_id":"621355","title":"KRI1 HOMOLOG; KRI1","url":"https://www.omim.org/entry/621355"},{"mim_id":"620875","title":"FIC DOMAIN-CONTAINING PROTEIN ADENYLYLTRANSFERASE; FICD","url":"https://www.omim.org/entry/620875"},{"mim_id":"620529","title":"RING FINGER PROTEIN 121; RNF121","url":"https://www.omim.org/entry/620529"},{"mim_id":"620521","title":"KELCH DOMAIN-CONTAINING PROTEIN 7B; KLHDC7B","url":"https://www.omim.org/entry/620521"},{"mim_id":"620391","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 16; PARP16","url":"https://www.omim.org/entry/620391"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":20.1}],"url":"https://www.proteinatlas.org/search/EIF2AK3"},"hgnc":{"alias_symbol":["PEK","PERK"],"prev_symbol":[]},"alphafold":{"accession":"Q9NZJ5","domains":[{"cath_id":"-","chopping":"106-226_233-272_307-364_371-417","consensus_level":"medium","plddt":75.6166,"start":106,"end":417},{"cath_id":"3.30.200.20","chopping":"588-675_880-891","consensus_level":"medium","plddt":82.0307,"start":588,"end":891},{"cath_id":"1.10.510.10","chopping":"892-965_984-1082","consensus_level":"medium","plddt":88.1868,"start":892,"end":1082}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZJ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZJ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZJ5-F1-predicted_aligned_error_v6.png","plddt_mean":59.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF2AK3","jax_strain_url":"https://www.jax.org/strain/search?query=EIF2AK3"},"sequence":{"accession":"Q9NZJ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZJ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZJ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZJ5"}},"corpus_meta":[{"pmid":"9819435","id":"PMC_9819435","title":"Identification 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/31023583","citation_count":284,"is_preprint":false},{"pmid":"19137072","id":"PMC_19137072","title":"Divergent effects of PERK and IRE1 signaling on cell viability.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19137072","citation_count":267,"is_preprint":false},{"pmid":"20453876","id":"PMC_20453876","title":"PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20453876","citation_count":253,"is_preprint":false},{"pmid":"17141632","id":"PMC_17141632","title":"PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis.","date":"2006","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17141632","citation_count":230,"is_preprint":false},{"pmid":"35228694","id":"PMC_35228694","title":"PERK is a critical metabolic hub for immunosuppressive function in macrophages.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35228694","citation_count":201,"is_preprint":false},{"pmid":"28499449","id":"PMC_28499449","title":"PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28499449","citation_count":158,"is_preprint":false},{"pmid":"15220213","id":"PMC_15220213","title":"Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.","date":"2004","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/15220213","citation_count":153,"is_preprint":false},{"pmid":"34168130","id":"PMC_34168130","title":"Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy.","date":"2021","source":"Nature 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of IRE1alpha and PERK in the unfolded protein response.","date":"2006","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16472110","citation_count":108,"is_preprint":false},{"pmid":"28148553","id":"PMC_28148553","title":"PERK activation mitigates tau pathology in vitro and in vivo.","date":"2017","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28148553","citation_count":102,"is_preprint":false},{"pmid":"22253692","id":"PMC_22253692","title":"Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22253692","citation_count":102,"is_preprint":false},{"pmid":"29230015","id":"PMC_29230015","title":"A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival.","date":"2017","source":"Nature cell 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kinases learn new tricks.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18418049","citation_count":78,"is_preprint":false},{"pmid":"26864318","id":"PMC_26864318","title":"PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development.","date":"2016","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26864318","citation_count":74,"is_preprint":false},{"pmid":"22125500","id":"PMC_22125500","title":"Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22125500","citation_count":70,"is_preprint":false},{"pmid":"30773986","id":"PMC_30773986","title":"Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30773986","citation_count":67,"is_preprint":false},{"pmid":"32204380","id":"PMC_32204380","title":"The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32204380","citation_count":67,"is_preprint":false},{"pmid":"38637497","id":"PMC_38637497","title":"IRE1 signaling increases PERK expression during chronic ER stress.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38637497","citation_count":65,"is_preprint":false},{"pmid":"31189710","id":"PMC_31189710","title":"Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway.","date":"2019","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31189710","citation_count":65,"is_preprint":false},{"pmid":"37536085","id":"PMC_37536085","title":"Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer.","date":"2023","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/37536085","citation_count":63,"is_preprint":false},{"pmid":"28440222","id":"PMC_28440222","title":"Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28440222","citation_count":61,"is_preprint":false},{"pmid":"33652720","id":"PMC_33652720","title":"PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33652720","citation_count":60,"is_preprint":false},{"pmid":"30668150","id":"PMC_30668150","title":"The PERK-EIF2α-ATF4 signaling branch regulates osteoblast differentiation and proliferation by PTH.","date":"2019","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30668150","citation_count":60,"is_preprint":false},{"pmid":"20850340","id":"PMC_20850340","title":"PERK in beta cell biology and insulin biogenesis.","date":"2010","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/20850340","citation_count":57,"is_preprint":false},{"pmid":"36216837","id":"PMC_36216837","title":"Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36216837","citation_count":56,"is_preprint":false},{"pmid":"28643372","id":"PMC_28643372","title":"Fine-tuning PERK signaling for neuroprotection.","date":"2017","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28643372","citation_count":56,"is_preprint":false},{"pmid":"15384883","id":"PMC_15384883","title":"Wolcott-Rallison syndrome: a clinical and genetic study of three children, 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CNPY2-PERK Pathway Induced by Hypoxia/Reoxygenation Injury.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31396081","citation_count":27,"is_preprint":false},{"pmid":"32215348","id":"PMC_32215348","title":"PERK Inhibition Mitigates Restenosis and Thrombosis: A Potential Low-Thrombogenic Antirestenotic Paradigm.","date":"2020","source":"JACC. 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neurons.","date":"2020","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/33341442","citation_count":24,"is_preprint":false},{"pmid":"32169212","id":"PMC_32169212","title":"Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK.","date":"2020","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/32169212","citation_count":24,"is_preprint":false},{"pmid":"27761878","id":"PMC_27761878","title":"Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis.","date":"2016","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/27761878","citation_count":24,"is_preprint":false},{"pmid":"36847967","id":"PMC_36847967","title":"PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIF2ɑ/ATF4/CHOP signaling.","date":"2023","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/36847967","citation_count":23,"is_preprint":false},{"pmid":"37022709","id":"PMC_37022709","title":"PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.","date":"2023","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37022709","citation_count":23,"is_preprint":false},{"pmid":"37166058","id":"PMC_37166058","title":"PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37166058","citation_count":22,"is_preprint":false},{"pmid":"34360909","id":"PMC_34360909","title":"The Role of PERK in Understanding Development of Neurodegenerative Diseases.","date":"2021","source":"International journal of molecular 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and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK).","date":"2018","source":"Reviews in the neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/29303785","citation_count":20,"is_preprint":false},{"pmid":"33870911","id":"PMC_33870911","title":"PERK mediates oxidative stress and adipogenesis in Graves' orbitopathy pathogenesis.","date":"2021","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33870911","citation_count":19,"is_preprint":false},{"pmid":"26872313","id":"PMC_26872313","title":"Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum.","date":"2016","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26872313","citation_count":19,"is_preprint":false},{"pmid":"32615282","id":"PMC_32615282","title":"Reciprocal regulation between GCN2 (eIF2AK4) and PERK (eIF2AK3) through the JNK-FOXO3 axis to modulate cancer drug resistance and clonal survival.","date":"2020","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32615282","citation_count":19,"is_preprint":false},{"pmid":"32054826","id":"PMC_32054826","title":"PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma.","date":"2020","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32054826","citation_count":18,"is_preprint":false},{"pmid":"36563857","id":"PMC_36563857","title":"Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36563857","citation_count":17,"is_preprint":false},{"pmid":"18216498","id":"PMC_18216498","title":"PERK-dependent regulation of HSP70 expression and the regulation of autophagy.","date":"2008","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/18216498","citation_count":17,"is_preprint":false},{"pmid":"34549728","id":"PMC_34549728","title":"PERK in POMC neurons connects celastrol with metabolism.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34549728","citation_count":16,"is_preprint":false},{"pmid":"36525128","id":"PMC_36525128","title":"CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.","date":"2022","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/36525128","citation_count":16,"is_preprint":false},{"pmid":"34314538","id":"PMC_34314538","title":"IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact 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requiring eIF-2α Ser-51.\",\n      \"method\": \"Recombinant protein produced in E. coli and Sf-9 insect cells; in vitro kinase assay; reticulocyte lysate translation assay; yeast complementation with eIF-2α Ser-51 mutant\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro kinase activity with substrate specificity, mutagenesis (Ser-51), functional rescue in yeast, and translation inhibition assay; multiple orthogonal methods in founding paper\",\n      \"pmids\": [\"9819435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A catalytic-dead point mutant of PEK (Lys-614→Ala) abolishes eIF-2α kinase activity but retains autophosphorylation when expressed in Sf-9 cells, demonstrating that autophosphorylation and substrate phosphorylation are mechanistically separable. PEK protein co-localizes with somatostatin in pancreatic delta cells.\",\n      \"method\": \"Site-directed mutagenesis; kinase assay in Sf-9 cells; immunohistochemistry co-localization with somatostatin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with in vitro kinase assay; single lab, two complementary methods\",\n      \"pmids\": [\"10026192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The N-terminal luminal domain of PERK/PEK is required for its activation by ER stress; deletion of these N-terminal sequences abolishes elevated PEK autophosphorylation and eIF-2α kinase activity during ER stress in mammalian cells.\",\n      \"method\": \"Deletion mutagenesis of N-terminal luminal sequences; eIF-2α kinase activity assay in mammalian cells under ER stress\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain-deletion mutagenesis with functional kinase assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"10677345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PERK activation during the UPR signals loss of cyclin D1 by increasing eIF-2α phosphorylation, thereby blocking cyclin D1 translation and causing G1-phase cell-cycle arrest. A truncated kinase-dead dominant-negative PERK attenuates cyclin D1 loss and cell-cycle arrest without compromising ER chaperone induction.\",\n      \"method\": \"Overexpression of wild-type and dominant-negative PERK; immunoblot for cyclin D1 and p-eIF2α; cell-cycle analysis by flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative genetics plus gain-of-function overexpression, reciprocal effects confirmed, specific mechanistic pathway (eIF2α→cyclin D1 translation) established\",\n      \"pmids\": [\"11035797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Loss-of-function mutations in EIF2AK3 (truncation removing the catalytic domain, and a missense mutation in the catalytic domain) segregate with Wolcott-Rallison syndrome, establishing that EIF2AK3 kinase activity is required for normal pancreatic beta-cell function and prevention of neonatal diabetes.\",\n      \"method\": \"Genetic mapping; sequencing of EIF2AK3 in affected families; functional inference from catalytic-domain truncation/missense\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics with loss-of-function alleles directly abolishing the catalytic domain; replicated across multiple families\",\n      \"pmids\": [\"10932183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense mutations in EIF2AK3 associated with Wolcott-Rallison syndrome produce proteins with complete loss of kinase activity (four mutants) or residual kinase activity (one mutant), as measured in vivo and in vitro; residual activity correlates with later onset of diabetes.\",\n      \"method\": \"In vitro and in vivo kinase activity assays of missense EIF2AK3 mutants; genotype-phenotype correlation\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay of disease-associated mutants; multiple mutants tested; genotype-phenotype correlation across multiple families\",\n      \"pmids\": [\"15220213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PERK is specifically required in insulin-secreting beta cells during fetal and early neonatal development for beta-cell proliferation, differentiation, and proinsulin trafficking; PERK expression in adult beta cells is not required to maintain glucose homeostasis, established by tissue-specific conditional knockout.\",\n      \"method\": \"Tissue- and cell-specific Perk conditional knockout mice; developmental analysis of beta-cell mass, proinsulin trafficking, and insulin secretion\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with defined cellular phenotypes; multiple independent conditional lines tested\",\n      \"pmids\": [\"17141632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of PERK function impairs ER-to-Golgi anterograde trafficking of proinsulin, retrotranslocation from the ER, and proteasomal degradation (ERAD); PERK is a positive regulator of ERAD and proteasomal activity in beta cells.\",\n      \"method\": \"Cell culture and mouse models with Perk impairment or gene-dosage modulation; proinsulin trafficking assays; proteasomal degradation assays; Ins2 Akita mouse epistasis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (KO, hypomorph, haploinsufficiency) with defined trafficking and degradation readouts; replicated in vivo and in vitro\",\n      \"pmids\": [\"20530744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PERK deficiency in mammary tumor cells impairs regeneration of intracellular antioxidants, causes accumulation of reactive oxygen species, and triggers oxidative DNA damage and DNA damage checkpoint activation, thereby impeding cell-cycle progression and tumor growth.\",\n      \"method\": \"Perk knockout in tumor cells; ROS measurement; DNA damage markers; cell-cycle analysis; animal mammary carcinoma model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation with specific ROS and DNA-damage readouts in vitro and in vivo; single lab, multiple methods\",\n      \"pmids\": [\"20453876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GSK2656157 is an ATP-competitive PERK kinase inhibitor (IC50 0.9 nM) that inhibits PERK autophosphorylation, eIF2α substrate phosphorylation, and downstream ATF4/CHOP induction in cells; oral dosing produces pharmacodynamic inhibition of PERK autophosphorylation in mouse pancreas.\",\n      \"method\": \"Biochemical ATP-competitive kinase assay; cellular phosphorylation assays; kinase selectivity panel (300 kinases); in vivo pharmacodynamic studies in mice\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous biochemical characterization including selectivity panel, cellular substrate phosphorylation, and in vivo PD; multiple orthogonal methods\",\n      \"pmids\": [\"23333938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PERK inhibits DNA replication during ER stress by promoting phosphorylation of the checkpoint adaptor Claspin and activation of Chk1 kinase, leading to replication fork slowing and reduced origin firing, independently of detectable DNA damage; Claspin depletion or Chk1 inhibition abolishes PERK-dependent DNA synthesis inhibition.\",\n      \"method\": \"PERK-dependent thapsigargin treatment; DNA synthesis assays; Claspin and Chk1 depletion/inhibition; replication origin firing analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic depletion of pathway components (PERK, Claspin, Chk1) with specific replication readouts; epistasis established across multiple orthogonal methods\",\n      \"pmids\": [\"27375025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PERK promotes degradation of cyclin D1 and p53 via the 26S proteasome during ER stress, representing a non-translational function of PERK in regulating protein stability.\",\n      \"method\": \"Overexpression/loss-of-function of PERK during ER stress; proteasome inhibitor experiments; protein stability assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — described as a demonstrated finding with pharmacological and genetic tools; single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"18418049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PERK induces expression of miR-211 upon UPR activation; miR-211 directly suppresses Bmal1 and Clock to produce a 10-hour phase shift in circadian oscillations, and repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation.\",\n      \"method\": \"miRNA profiling; miR-211 target validation; luciferase reporter assays; PERK genetic manipulation; protein synthesis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PERK genetic manipulation linked to miR-211 induction and direct circadian regulator suppression; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29230015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CNPY2 (canopy homolog 2) is released from GRP78 upon ER stress and engages PERK to induce CHOP expression, initiating the UPR; CNPY2 deletion blocks the PERK-CHOP pathway in vivo.\",\n      \"method\": \"Co-immunoprecipitation of CNPY2 with PERK; CNPY2 knockout mice; CHOP pathway reporter assays; liver damage model\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP binding, in vivo genetic deletion, and functional pathway reporter; multiple orthogonal methods with in vivo validation\",\n      \"pmids\": [\"28869608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PERK drives cancer invasion and metastasis through the transcription factor CREB3L1, which acts downstream of PERK specifically in mesenchymal triple-negative breast cancer cells; inhibition of CREB3L1 suppresses PERK-dependent invasion.\",\n      \"method\": \"PERK and CREB3L1 genetic manipulation; invasion and metastasis assays in vitro and in vivo; epistasis placing CREB3L1 downstream of PERK\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in cell and animal models; single lab, multiple experimental approaches\",\n      \"pmids\": [\"29057869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DLK (Dual Leucine Zipper Kinase) activates PERK signaling in neurons in response to nerve injury and neurotrophin deprivation, leading to ATF4 upregulation via the ISR; disruption of PERK signaling delays neurodegeneration without reducing JNK signaling, placing PERK downstream of DLK in a neuronal stress pathway.\",\n      \"method\": \"Mouse nerve injury models; DLK and PERK genetic manipulation; ATF4 measurement; JNK and PERK pathway epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple injury models and pathway dissection; single lab, multiple complementary approaches\",\n      \"pmids\": [\"28440222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PERK regulates proinsulin proteostasis not by controlling synthesis rates (global protein and proinsulin synthesis are both down-regulated in PERK-inhibited cells) but by modulating ER chaperones BiP and ERp72; ERp72 overexpression rescues proinsulin aggregation whereas BiP manipulation promotes it.\",\n      \"method\": \"PERK inhibition in cell culture and mice; high-resolution imaging; protein fractionation; immunological assays; BiP and ERp72 overexpression/knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, fractionation, genetic rescue/knockdown) in multiple model systems; definitively negates a prior hypothesis and establishes chaperone regulation as mechanism\",\n      \"pmids\": [\"29444822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BiP interaction with the luminal domains of PERK (and IRE1) switches BiP from its chaperone ATPase cycle into an ER stress sensor cycle by preventing co-chaperone binding and loss of ATPase stimulation; misfolded protein-dependent dissociation of BiP from PERK/IRE1 is primed by ATP but not ADP.\",\n      \"method\": \"Reconstitution of human UPR components in vitro; biochemical co-chaperone binding assays; ATPase stimulation assays; nucleotide (ATP vs ADP) dependence experiments\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of human components with mechanistic nucleotide and co-chaperone competition assays; multiple orthogonal biochemical methods\",\n      \"pmids\": [\"31695187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMAO (trimethylamine N-oxide) directly binds to PERK at physiologically relevant concentrations and selectively activates the PERK branch of the UPR, inducing FoxO1 in a PERK-dependent manner; interventions reducing TMAO reduce PERK activation and FoxO1 levels in liver.\",\n      \"method\": \"Direct TMAO-PERK binding assay; selective UPR branch activation assays; PERK-dependent FoxO1 induction; gut microbiota manipulation and FMO3 inhibition experiments in vivo\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding demonstrated plus functional selectivity assays and in vivo epistasis; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"31543404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PERK activation during ER stress and glucose deprivation stimulates formation of respiratory chain supercomplexes (SCs) through the PERK-eIF2α-ATF4 axis, which increases SCAF1 (COX7A2L) expression; PERK ablation suppresses SC levels and oxidative phosphorylation-dependent ATP production.\",\n      \"method\": \"Genetic ablation and pharmacological inhibition of PERK; measurement of SC levels; SCAF1 expression; OXPHOS ATP production; PERK activation in mitochondrial disease patient cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological PERK manipulation with mechanistic downstream pathway (ATF4→SCAF1→SCs) established; multiple model systems\",\n      \"pmids\": [\"31023583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PERK-dependent translational inhibition extends beyond global translation to specifically repress ER-targeted proteins (transmembrane, glycoproteins, disulfide-bond-containing) via ribosome footprint profiling; PERK also attenuates expression of a subset of XBP1-ATF6 UPR targets, demonstrating cross-talk between UPR branches.\",\n      \"method\": \"Ribosome footprint profiling (Ribo-seq) in WT vs PERK-/- mouse embryonic fibroblasts; RNA-seq; ER stress time-course experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome footprint profiling in genetic null cells with global and selective repression analysis; single lab, genome-wide method\",\n      \"pmids\": [\"30867432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Thrombospondin-1 (Thbs1) directly binds and activates PERK, inducing its downstream transcription factor ATF4 and causing autophagy-mediated lethal cardiac atrophy; genetic deletion of PERK in Thbs1 transgenic mice blunts ATF4 induction, autophagy, and cardiac atrophy.\",\n      \"method\": \"Co-immunoprecipitation of Thbs1 and PERK; Thbs1 transgenic mice; Perk cardiac-specific knockout; ATF4 and autophagy marker measurement; AAV9 gene transfer of PERK and ATF4\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP binding plus genetic ablation (PERK KO rescues lethal phenotype) and gain-of-function (AAV9-PERK reproduces atrophy); multiple orthogonal methods in vivo\",\n      \"pmids\": [\"34168130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The oxidoreductase ERO1α covalently interacts with PERK upon ER stress (tunicamycin treatment), requiring the C-terminal active site of ERO1α and cysteine 216 of PERK; the PERK-ERO1α complex promotes oxidization of mitochondria-ER contact (MERC) proteins, controls mitochondrial dynamics, and improves ER-mitochondria Ca2+ flux to maintain bioenergetics.\",\n      \"method\": \"Co-immunoprecipitation; cysteine mutagenesis (C216 of PERK); proteinaceous Ca2+ probes at MERC; mitochondrial dynamics imaging; bioenergetic assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — covalent interaction identified with site-specific mutagenesis (C216), functional consequences on MERC and Ca2+ flux measured with orthogonal methods; single lab, multiple rigorous approaches\",\n      \"pmids\": [\"36586409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PERK mediates immunosuppressive M2 macrophage activation and proliferation downstream of IL-4 and tumor microenvironment signals, acting through the PERK-ATF4 axis to upregulate PSAT1 (phosphoserine aminotransferase 1) and serine biosynthesis; increased serine leads to enhanced α-ketoglutarate production required for JMJD3-dependent epigenetic modification.\",\n      \"method\": \"PERK knockout/inhibition in macrophages; metabolomics; ATF4 and PSAT1 genetic manipulation; α-ketoglutarate and JMJD3 assays; in vivo tumor models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with metabolomic and epigenetic pathway dissection; multiple orthogonal methods and in vivo validation\",\n      \"pmids\": [\"35228694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PERK in hematopoietic stem/progenitor cells (HSPCs) in the spleen reprograms HSPCs into committed MDSC precursors via PERK-ATF4-C/EBPβ signaling; pharmacological or genetic PERK inhibition in HSPCs prevents myeloid descendants from becoming MDSCs.\",\n      \"method\": \"Genetic and pharmacological PERK inhibition in murine and human HSPCs; spleen-targeted PERK antagonist delivery; tumor models; MDSC functional assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological manipulation in multiple in vitro and in vivo models; pathway dissection via ATF4-C/EBPβ; single lab\",\n      \"pmids\": [\"35266960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) during acute ER stress, requiring YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1; accumulated outer-mitochondrial-membrane PA inhibits mitochondrial fission and induces protective mitochondrial elongation.\",\n      \"method\": \"PERK genetic ablation and activation; PA lipid measurements; YME1L and PRELID1 genetic manipulation; mitochondrial morphology imaging; fission assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (PERK→YME1L→PRELID1→PA→elongation) with lipid measurements and morphology readouts; multiple orthogonal methods\",\n      \"pmids\": [\"37306086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATAD3A (mitochondrial ATPase AAA domain-containing protein 3A) interacts with PERK and competes for binding with PERK's target eIF2, forming mitochondria-ER contact sites; during ER stress PERK-ATAD3A interactions increase, attenuating local PERK signaling at mitochondria and protecting active translation there from ER stress-induced repression.\",\n      \"method\": \"Live-cell imaging of reporter mRNA translation; Co-immunoprecipitation of PERK-ATAD3A; competition binding assay with eIF2; ATAD3A knockdown; PERK-ATAD3A proximity ligation at mitochondria-ER contacts\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — live-cell translation imaging, Co-IP, competition binding, and localization at MERCs; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39116259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM29 interacts with PERK and promotes SUMOylation of PERK to maintain its protein stability, thereby sustaining PERK-mediated signaling pathways in cardiomyocytes during viral infection; TRIM29 loss reduces PERK stability and PERK-mediated ER stress responses.\",\n      \"method\": \"Co-immunoprecipitation of TRIM29 and PERK; SUMOylation assays; TRIM29 knockout mice; viral myocarditis model; PERK stability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding, post-translational modification (SUMOylation) identified, in vivo genetic model; single lab, multiple methods\",\n      \"pmids\": [\"38664417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-204 directly targets the 3′UTR of PERK mRNA and reduces PERK protein expression and downstream ATF4/CHOP signaling in beta cells; miR-204-mediated PERK inhibition exacerbates ER stress-induced beta-cell apoptosis.\",\n      \"method\": \"3′UTR luciferase reporter assay; miR-204 overexpression in primary human islets, mouse islets, and INS-1 cells; immunoblot for PERK and downstream targets; cell death assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3′UTR targeting validated by reporter assay, confirmed in primary human tissue; single lab, multiple cell types\",\n      \"pmids\": [\"27384111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXO3 directly binds the PERK promoter and transcriptionally activates PERK expression, as confirmed by ChIP, siRNA knockdown, overexpression assays, and Foxo1/3/4-/- MEFs; PERK is thus a direct transcriptional downstream target of FOXO3.\",\n      \"method\": \"ChIP; siRNA knockdown; FOXO3 overexpression; Foxo1/3/4 triple-knockout MEFs; RT-qPCR and immunoblot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding; validated in genetic null cells; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31312024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JEV non-structural protein NS4B binds PERK via its LIG-FHA and LIG-WD40 domains (both required), inducing PERK dimerization, which is the mechanistic basis of JEV-induced PERK activation leading to the PERK-ATF4-CHOP apoptosis pathway.\",\n      \"method\": \"Co-immunoprecipitation of NS4B with PERK; glycerol gradient centrifugation for PERK dimerization; domain-deletion mutagenesis of NS4B; PERK inhibitor experiments in vitro and in vivo\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding with domain mapping and dimerization assay; single lab with complementary methods\",\n      \"pmids\": [\"31189710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTH induces ER stress in osteoblasts through the PERK-eIF2α-ATF4 signaling pathway; HSP90 interacts with PERK and maintains PERK protein stabilization early during PTH-induced ER stress; HSP90 inhibition decreases PERK protein expression and inhibits osteoblast differentiation and proliferation upon PTH treatment.\",\n      \"method\": \"PERK/ATF4 siRNA and pharmacological inhibitors; co-immunoprecipitation of HSP90 with PERK; geldanamycin (HSP90 inhibitor) treatment; osteoblast differentiation and proliferation assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies HSP90-PERK interaction; functional consequences confirmed by HSP90 inhibitor; single lab, multiple methods\",\n      \"pmids\": [\"30668150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mfn2 physically interacts with PERK at mitochondria-associated ER membranes (MAMs); high glucose promotes a decrease in the Mfn2-PERK interaction; Mfn2 silencing activates the PERK pathway and increases podocyte apoptosis, while PERK inhibition protects mitochondrial function without affecting Mfn2 expression, placing PERK downstream of Mfn2 at MAMs.\",\n      \"method\": \"Co-immunoprecipitation of Mfn2 and PERK; Mfn2 siRNA knockdown; PERK inhibitor treatment; MAM ultrastructure analysis; mitochondrial function assays in podocytes\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding with genetic epistasis (Mfn2→PERK) established by knockdown and inhibitor; single lab, multiple methods\",\n      \"pmids\": [\"34988075\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF2AK3/PERK is an ER-resident transmembrane serine/threonine kinase that autophosphorylates and phosphorylates eIF-2α on Ser-51 to inhibit global translation during ER stress; its luminal domain senses unfolded proteins (switching BiP from chaperone to sensor mode), and upon activation it signals through eIF2α-ATF4-CHOP to orchestrate translational repression, cell-cycle arrest (via cyclin D1 loss), mitochondrial bioenergetics (respiratory supercomplex assembly, PA remodeling for elongation, PERK-ERO1α covalent complex for Ca2+ flux), and selective autophagy regulation, while its activity is regulated by binding partners including BiP, Thbs1, CNPY2, HSP90, ATAD3A, Mfn2, ERO1α, and TRIM29 (which SUMOylates PERK to stabilize it), with loss-of-function mutations causing Wolcott-Rallison syndrome through impaired beta-cell proliferation, differentiation, and ER chaperone-dependent proinsulin quality control.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EIF2AK3 (PERK) is an ER-resident eIF-2\\u03b1 kinase that couples sensing of ER stress to translational and transcriptional reprogramming of the cell. It autophosphorylates on serine/threonine residues and specifically phosphorylates eIF-2\\u03b1 on Ser-51 to inhibit translation, with autophosphorylation and substrate phosphorylation being mechanistically separable functions [#0, #1]. Its N-terminal luminal domain is required for activation during ER stress [#2], a step gated by BiP, which switches from its chaperone ATPase cycle into a stress-sensor cycle through interaction with the PERK luminal domain and dissociates from PERK upon accumulation of misfolded proteins [#17]. Activated PERK signals predominantly through the eIF2\\u03b1-ATF4 axis to drive diverse outcomes: G1 cell-cycle arrest via loss of cyclin D1 translation [#3], replication-fork slowing through Claspin/Chk1 [#10], redox and antioxidant homeostasis [#8], and a broad mitochondrial program including respiratory supercomplex assembly via ATF4-SCAF1 [#19], adaptive phosphatidic-acid remodeling driving protective mitochondrial elongation [#25], and a covalent PERK-ERO1\\u03b1 complex at mitochondria-ER contacts that controls Ca2+ flux and bioenergetics [#22]. In pancreatic beta cells PERK is required during fetal and neonatal development for proliferation, differentiation, and proinsulin proteostasis, the latter mediated through control of ER chaperones BiP and ERp72 and through positive regulation of ERAD rather than synthesis rate [#6, #7, #16]. Loss-of-function mutations in EIF2AK3 that abolish or reduce kinase activity cause Wolcott-Rallison syndrome, with residual activity correlating with later-onset neonatal diabetes [#4, #5]. PERK activity is tuned by an array of binding partners and upstream activators, including CNPY2, Thbs1, the viral protein NS4B, and the metabolite TMAO that act as activators [#13, #21, #30, #18], and by HSP90, TRIM29, ATAD3A, and Mfn2 that regulate its stability, localization, and local signaling [#31, #27, #26, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that PERK is a bona fide eIF-2\\u03b1 kinase defined the molecular activity that anchors all downstream biology.\",\n      \"evidence\": \"Recombinant kinase produced in E. coli/Sf-9, in vitro kinase assay with Ser-51 specificity, reticulocyte translation assay, and yeast GCN2 complementation\",\n      \"pmids\": [\"9819435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how the kinase is activated in cells\", \"No structural basis for substrate recognition\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Separating autophosphorylation from substrate phosphorylation and localizing PERK to pancreatic delta cells clarified its catalytic logic and tissue distribution.\",\n      \"evidence\": \"Lys-614\\u2192Ala active-site mutant in Sf-9 cells; immunohistochemical co-localization with somatostatin\",\n      \"pmids\": [\"10026192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Delta-cell co-localization did not establish a delta-cell function\", \"Mechanism linking autophosphorylation to substrate phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the luminal domain as the ER-stress activation module placed PERK as a transmembrane stress sensor.\",\n      \"evidence\": \"Deletion of N-terminal luminal sequences abolishing stress-induced autophosphorylation and kinase activity in mammalian cells\",\n      \"pmids\": [\"10677345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the luminal ligand or sensing mechanism\", \"Single domain-deletion approach\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linking PERK to cyclin D1 loss and G1 arrest, and to Wolcott-Rallison syndrome, connected the kinase to cell-cycle control and human disease.\",\n      \"evidence\": \"Dominant-negative/overexpression PERK with cyclin D1 immunoblot and flow cytometry; genetic mapping and sequencing of EIF2AK3 in WRS families\",\n      \"pmids\": [\"11035797\", \"10932183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disease mapping inferred kinase requirement without functional assay of all alleles\", \"Cell-cycle mechanism shown in overexpression context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Functionally testing WRS-associated missense alleles established kinase activity as the disease-relevant output and produced a genotype-phenotype dose relationship.\",\n      \"evidence\": \"In vitro and in vivo kinase assays of five missense mutants with genotype-phenotype correlation\",\n      \"pmids\": [\"15220213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the beta-cell-specific cellular defect\", \"Residual-activity threshold for disease onset not defined mechanistically\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Conditional knockout showed PERK acts developmentally in beta cells, dissociating its requirement in fetal/neonatal beta-cell biology from adult glucose homeostasis.\",\n      \"evidence\": \"Tissue- and cell-specific Perk conditional knockout mice with beta-cell mass, proinsulin trafficking, and secretion analysis\",\n      \"pmids\": [\"17141632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of trafficking defect not yet defined\", \"Why adult beta cells tolerate PERK loss unexplained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two studies extended PERK function to ERAD/proteasomal trafficking in beta cells and to antioxidant/ROS control in tumor cells, broadening its proteostatic and redox roles.\",\n      \"evidence\": \"Perk genetic models with proinsulin trafficking and ERAD assays (Ins2 Akita epistasis); Perk knockout tumor cells with ROS, DNA-damage, and cell-cycle readouts\",\n      \"pmids\": [\"20530744\", \"20453876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PERK substrate(s) in ERAD regulation unidentified\", \"How translational control produces antioxidant regeneration not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Development of a selective ATP-competitive inhibitor provided a pharmacological tool validating PERK catalytic output in cells and in vivo.\",\n      \"evidence\": \"GSK2656157 biochemical assay (IC50 0.9 nM), 300-kinase selectivity panel, cellular phosphorylation, and mouse pharmacodynamics\",\n      \"pmids\": [\"23333938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Off-target effects in chronic settings not addressed\", \"Does not distinguish translational from non-translational PERK functions\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"PERK was shown to enforce a replication checkpoint via Claspin/Chk1 and to be negatively regulated by miR-204, refining its cell-cycle and expression control.\",\n      \"evidence\": \"Thapsigargin-induced PERK signaling with Claspin/Chk1 depletion and replication assays; miR-204 3\\u2032UTR luciferase reporter in human/mouse islets and INS-1 cells\",\n      \"pmids\": [\"27375025\", \"27384111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PERK promotes Claspin phosphorylation mechanistically unclear\", \"Physiological signals controlling miR-204 in vivo not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies expanded the PERK interactome and downstream effectors, identifying CNPY2 as an activator and CREB3L1, miR-211, and proteasomal cyclin D1/p53 degradation as outputs in stress, circadian, and cancer contexts.\",\n      \"evidence\": \"Co-IP and CNPY2 knockout mice; PERK genetic manipulation with CREB3L1 invasion assays, miR-211/Bmal1-Clock reporter assays, and proteasome stability assays\",\n      \"pmids\": [\"28869608\", \"29057869\", \"29230015\", \"18418049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these branches are cell-type specific or general unresolved\", \"Direct biochemical link from PERK to each effector incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying DLK as a neuronal upstream activator of PERK placed the kinase in an injury-responsive integrated stress pathway.\",\n      \"evidence\": \"Mouse nerve-injury models with DLK/PERK genetic manipulation, ATF4 measurement, and JNK/PERK epistasis\",\n      \"pmids\": [\"28440222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which DLK activates PERK not defined\", \"Single neuronal injury context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mechanistic dissection in beta cells showed PERK controls proinsulin proteostasis through ER chaperones rather than synthesis rate, refuting a synthesis-control model.\",\n      \"evidence\": \"PERK inhibition in cells/mice with imaging, fractionation, and BiP/ERp72 overexpression-knockdown rescue\",\n      \"pmids\": [\"29444822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PERK signaling modulates ERp72/BiP levels unresolved\", \"Whether the same logic applies outside beta cells unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A cluster of studies reconstituted BiP-mediated luminal sensing, identified TMAO as a direct activating ligand, FOXO3 as a transcriptional inducer, JEV NS4B as a dimerization-driving viral activator, and HSP90 as a stabilizing partner, defining how PERK is switched on and maintained.\",\n      \"evidence\": \"In vitro reconstitution of BiP/PERK ATPase and co-chaperone competition; TMAO binding and PERK-dependent FoxO1 assays; FOXO3 ChIP and triple-KO MEFs; NS4B Co-IP/domain mapping and glycerol-gradient dimerization; HSP90 Co-IP with geldanamycin\",\n      \"pmids\": [\"31695187\", \"31543404\", \"31312024\", \"31189710\", \"30668150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BiP, ligand, and partner inputs are integrated or independent unresolved\", \"Structural details of dimerization-driven activation incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-wide and mitochondrial studies showed PERK selectively represses ER-targeted protein translation and drives respiratory supercomplex assembly, expanding its role beyond global translational shutdown into mitochondrial bioenergetics.\",\n      \"evidence\": \"Ribo-seq/RNA-seq in WT vs PERK-/- MEFs; PERK ablation/inhibition with supercomplex, SCAF1, and OXPHOS ATP measurements\",\n      \"pmids\": [\"30867432\", \"31023583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How selectivity for ER-targeted transcripts is achieved unclear\", \"Direct vs indirect control of SCAF1 by ATF4 not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Thbs1 was identified as a direct PERK activator driving lethal autophagy-mediated cardiac atrophy, extending PERK's ligand-activated biology to the heart.\",\n      \"evidence\": \"Thbs1-PERK Co-IP, Thbs1 transgenic and cardiac-specific Perk knockout mice, and AAV9-PERK/ATF4 gene transfer\",\n      \"pmids\": [\"34168130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical nature of Thbs1-PERK binding not structurally defined\", \"How a secreted matricellular protein engages an ER-luminal sensor unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Studies in immune cells and mitochondria established PERK-ATF4 metabolic-epigenetic reprogramming in macrophages and MDSC precursors and a covalent PERK-ERO1\\u03b1 complex controlling MERC Ca2+ flux.\",\n      \"evidence\": \"PERK KO/inhibition in macrophages and HSPCs with metabolomics, PSAT1/ATF4/C-EBP\\u03b2 dissection, tumor models; ERO1\\u03b1-PERK Co-IP with C216 mutagenesis and MERC Ca2+ probes\",\n      \"pmids\": [\"35228694\", \"35266960\", \"36586409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether immune and mitochondrial branches share regulatory inputs unknown\", \"How covalent ERO1\\u03b1-PERK linkage forms in vivo not fully characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mfn2 was identified as a MAM-localized partner placing PERK downstream of mitochondrial dynamics control in podocyte injury.\",\n      \"evidence\": \"Mfn2-PERK Co-IP, Mfn2 siRNA, PERK inhibition, and MAM ultrastructure/mitochondrial function assays in podocytes\",\n      \"pmids\": [\"34988075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Mfn2 directly suppresses PERK or via tethering unclear\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PERK was shown to remodel mitochondrial phosphatidic acid via YME1L-PRELID1 to drive protective mitochondrial elongation, defining a lipid-based mitochondrial adaptation.\",\n      \"evidence\": \"PERK ablation/activation with PA measurements, YME1L/PRELID1 manipulation, and mitochondrial morphology/fission assays\",\n      \"pmids\": [\"37306086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PERK signaling controls YME1L activity unresolved\", \"Whether this axis operates in beta cells or disease unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ATAD3A and TRIM29 were identified as regulators that locally attenuate PERK signaling at MERCs and stabilize PERK by SUMOylation, respectively, revealing spatial and post-translational control of the kinase.\",\n      \"evidence\": \"ATAD3A-PERK Co-IP, eIF2 competition binding, live-cell translation imaging, and MERC proximity ligation; TRIM29-PERK Co-IP, SUMOylation assays, and TRIM29 knockout viral myocarditis mice\",\n      \"pmids\": [\"39116259\", \"38664417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATAD3A competition is dynamically regulated during stress unclear\", \"SUMO acceptor sites on PERK not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many luminal activators, cytosolic stabilizers, and spatial regulators are integrated to set PERK signaling thresholds across tissues, and the structural basis of luminal sensing, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified structural model of luminal-domain activation\", \"Tissue-specific selection among ATF4-dependent output branches undefined\", \"Relative contribution of translational vs non-translational PERK functions in vivo unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 5, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 16, 17]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [22, 25, 26, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2, 13, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 16, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 23, 25]}\n    ],\n    \"complexes\": [\n      \"PERK-ERO1\\u03b1 covalent complex\",\n      \"mitochondria-ER contact sites (MERC/MAM)\"\n    ],\n    \"partners\": [\n      \"BiP\",\n      \"CNPY2\",\n      \"THBS1\",\n      \"ERO1\\u03b1\",\n      \"ATAD3A\",\n      \"HSP90\",\n      \"MFN2\",\n      \"TRIM29\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}