{"gene":"KRT8","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2011,"finding":"K8 and K18 form homogeneous tetrameric complexes when mixed and renatured together (confirmed by analytical ultracentrifugation and sedimentation equilibrium), and these tetramers serve as starter units for rapid filament assembly; K8/K18 filaments assemble several times faster than vimentin and desmin, with a persistence length of ~300 nm that increases to ~480 nm upon addition of MgCl2.","method":"Recombinant protein reconstitution, analytical ultracentrifugation, sedimentation equilibrium centrifugation, electron microscopy, in vitro filament assembly kinetics","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro from recombinant proteins with multiple orthogonal biophysical methods (AUC, sedimentation equilibrium, EM, length profiling)","pmids":["22085677"],"is_preprint":false},{"year":2015,"finding":"Hydrogen-deuterium exchange mass spectrometry of K8/K18 complexes revealed that IF-consensus motifs at the ends of the central α-helical rod segment (mediating head-to-tail dimer-dimer interaction) become distinctly more protected upon filament formation, while some coiled-coil regions remain dynamic; K8 forms dimers/tetramers alone whereas K18 is monomeric alone.","method":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) of recombinant K8/K18 at various assembly states","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — HDX-MS is a direct structural/dynamics method applied to multiple assembly states with rigorous controls","pmids":["26434626"],"is_preprint":false},{"year":1992,"finding":"KRT8 (CK8) is phosphorylated by protein kinase C (PKC) in primary hepatocytes; TPA (a PKC activator) transiently increases CK8 phosphorylation within 15 min, an effect abolished after PKC down-regulation, identifying CK8 as an in vivo PKC substrate. CK18 phosphorylation was not increased by TPA under the same conditions.","method":"Metabolic phosphorylation labeling, TPA/PKC pharmacological manipulation in primary mouse hepatocytes, indirect immunofluorescence","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with PKC activator/down-regulation plus morphological readout, single lab","pmids":["1283312"],"is_preprint":false},{"year":2001,"finding":"In CK8-null mouse intestinal villus enterocytes (the only cell type completely lacking IFs), apical membrane proteins (alkaline phosphatase, sucrase-isomaltase, CFTR) were lost progressively along the villus, syntaxin 3 was absent, and γ-tubulin was mislocalized from its normal sub-apical position, with disorganized microtubules — establishing a role for KRT8-containing intermediate filaments in organizing the apical domain of simple polarized epithelia.","method":"CK8-knockout mouse model, immunofluorescence localization of apical markers and cytoskeletal components in intestinal epithelia","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple specific molecular readouts (apical proteins, syntaxin 3, γ-tubulin, microtubules) in vivo","pmids":["11171325"],"is_preprint":false},{"year":2015,"finding":"TNF-α induces ectopic expression of K8 and K18 in cardiomyocytes via NF-κB signaling; in desmin-deficient mice, the resulting K8/K18 network localizes primarily at intercalated discs and confers cardioprotection by maintaining normal intercalated disc structure and mitochondrial integrity and function. Loss of the K8/K18 network led to maladaptive cardiac phenotype after pressure overload.","method":"Genetic (desmin-KO, TNF-α overexpression) mouse models, NF-κB pathway analysis, transverse aortic constriction, electron microscopy, mitochondrial function assays, immunofluorescence","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models, loss-of-function (K8/K18 network ablation), gain-of-function (ectopic induction), and mechanistic link to NF-κB with functional cardiac readouts","pmids":["26280121"],"is_preprint":false},{"year":2012,"finding":"Loss of plakophilin3 (PKP3) leads to increased PRL3 phosphatase levels, which decreases phosphorylation of K8, stabilizing K8 filaments and increasing K8 protein levels; stabilized K8 promotes cell migration, lamellipodia formation, colony formation in soft agar, and tumorigenesis/metastasis in nude mice. K8 knockdown in the PKP3-knockdown background reverses these phenotypes.","method":"shRNA knockdown of PKP3 and K8 in HCT116 cells, Western blotting for K8 phosphorylation and PRL3, wound-healing/migration assays, soft agar colony formation, nude mouse xenografts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double knockdown rescue), multiple functional readouts, single lab","pmids":["22701666"],"is_preprint":false},{"year":2017,"finding":"In retinal pigment epithelial (RPE) cells under oxidative stress, KRT8 upregulation (promoted by autophagy) is cytoprotective, whereas phosphorylation of KRT8 by MAPK1/ERK2 and MAPK3/ERK1 drives pathological epithelial-mesenchymal transition (EMT). Inhibition of autophagy further promotes EMT, which is reversible by MAPK inhibition.","method":"Autophagy inhibition, MAPK pharmacological inhibition, siRNA knockdown, Western blotting, immunofluorescence in RPE cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic interventions, identified specific kinases (ERK1/2), single lab","pmids":["28045574"],"is_preprint":false},{"year":2020,"finding":"KRT8 phosphorylation (at critical phosphorylated site) impairs autophagosome-lysosome fusion; mutagenesis of the phosphorylation site or KRT8 knockdown causes autophagy impairment in RPE cells undergoing TGF-β2-induced EMT, and phosphorylated KRT8 is detected in epiretinal/subretinal membranes of PVR patients.","method":"Site-directed mutagenesis of KRT8 phosphorylation site, siRNA knockdown, pharmacological autophagy inhibition, Western blot, immunofluorescence in RPE cells and patient membranes","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation site with specific functional readout (autophagosome-lysosome fusion), single lab","pmids":["32022439"],"is_preprint":false},{"year":2021,"finding":"KRT8 physically interacts with the cytolinker protein PLEC (plectin) and through this interaction associates with mitochondria; this KRT8-PLEC association facilitates mitochondrial fission-mediated mitophagy in RPE cells under oxidative stress, suppressing accumulation of damaged mitochondria and necrotic cell death. KRT8 phosphorylation under oxidative stress diminishes the PLEC-mitochondria-KRT8 association.","method":"Co-immunoprecipitation (KRT8-PLEC interaction), mitochondrial morphology imaging, mitophagy flux assays, KRT8/PLEC knockdown, oxidative stress model in RPE cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, KO/KD with specific mitophagy and cell-death readouts, single lab","pmids":["33783309"],"is_preprint":false},{"year":2023,"finding":"Excessive mechanical load activates RHOA-PKN (protein kinase N), which phosphorylates KRT8 on Ser43; this phosphorylation impedes trafficking of Golgi-resident RAB33B, suppresses autophagosome initiation, and contributes to intervertebral disc degeneration (IDD). Conditional knockout of Krt8 in nucleus pulposus aggravates load-induced IDD in vivo, while KRT8 overexpression confers resistance. Knockdown of PKN1/PKN2 at early IDD stage ameliorates degeneration.","method":"Conditional KO mouse, AAV-mediated KRT8 overexpression, site-specific phosphorylation assays (Ser43), RHOA-PKN pathway analysis, RAB33B trafficking assays, in vivo IDD models (lumbar instability, tail compression)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identified specific phosphorylation site (Ser43), identified writer kinase (PKN), downstream effector (RAB33B/autophagosome initiation), validated in vivo KO and OE with functional disc degeneration readouts","pmids":["36897022"],"is_preprint":false},{"year":2013,"finding":"Compressive mechanical loads applied to nucleus pulposus cells cause time- and dose-dependent phosphorylation and disassembly of CK8, mediated by activation of protein kinase C (PKC). In human IDD tissue, CK8 expression is decreased with increased phosphorylation.","method":"In vitro compressive loading of NP cells, PKC inhibitor studies, Western blotting for phospho-CK8, human IDD tissue analysis","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological PKC inhibition establishes PKC as mediator, dose/time dependence of mechanical loading, corroborated by human tissue; single lab","pmids":["24166186"],"is_preprint":false},{"year":1997,"finding":"Transfection of K8 into a vimentin-expressing pancreatic adenocarcinoma (no endogenous keratins) stabilized endogenous K19 and formed K8/K19 filaments; K8 expression increased cell motility and tumor growth, contrasting with K18 (which suppressed tumorigenicity). K18 required co-expression with K8 for stabilization.","method":"Stable transfection of K8 and K18 into BSp73 adenocarcinoma cells, soft agar growth assays, motility assays, syngeneic tumor formation in animals","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function transfection with multiple functional readouts (migration, tumor growth), single lab","pmids":["9152022"],"is_preprint":false},{"year":2016,"finding":"In vitro, potassium ions induce bundling of K8/K18 filaments and significantly stiffen the network, while the cytolinker plectin crosslinks filaments at intersection points without bundle formation but increases network rigidity at concentrations above ~20% of cellular plectin levels. In situ, plectin downregulation to ~10% significantly decreases cell stiffness of IF-containing cytoskeletons.","method":"In vitro K8/K18 network assembly with potassium ions and recombinant plectin, microrheology, atomic force microscopy on detergent-extracted A431 cells with plectin siRNA knockdown","journal":"Soft matter","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — reconstituted in vitro networks plus in situ functional mechanics, single lab with two orthogonal methods","pmids":["27489177"],"is_preprint":false},{"year":2011,"finding":"KRT8 (but not KRT18) genetic variants are associated with CFTR-mediated residual chloride secretion in F508del-CFTR homozygous cystic fibrosis patients and with CF disease severity, suggesting that K8/K18 heterodimeric intermediate filaments are required for proper CFTR targeting to the apical membrane in epithelial cells.","method":"Candidate gene association study with SNP haplotyping in contrasting CF patient subpopulations stratified by disease severity and CFTR chloride secretion","journal":"BMC medical genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic association only; no direct molecular or cellular experiment establishing the mechanism; functional inference is indirect","pmids":["21548936"],"is_preprint":false},{"year":2024,"finding":"NAT10 (N-acetyltransferase 10) stabilizes KRT8 mRNA by catalyzing N4-acetylcytidine (ac4C) modification of KRT8 mRNA, increasing KRT8 protein levels and thereby promoting epithelial-mesenchymal transition and cell migration in prostate cancer cells.","method":"NAT10 knockdown/overexpression, acRIP-seq (ac4C RNA immunoprecipitation sequencing) to identify KRT8 mRNA as NAT10 target, mRNA stability assays, EMT marker analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C modification of KRT8 mRNA identified by acRIP-seq with functional validation (mRNA stability, EMT), single lab","pmids":["38922788"],"is_preprint":false},{"year":2017,"finding":"KRT8 overexpression in gastric cancer cells activates Integrinβ1-FAK-induced EMT signaling, and KRT8 overexpression increases p-Smad2/3 levels, placing KRT8 upstream of TGFβ-dependent signaling events and EMT.","method":"KRT8 overexpression and siRNA knockdown in gastric cancer cell lines, Western blotting for Integrinβ1-FAK and p-Smad2/3, migration assays","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by Western blot without direct mechanistic reconstitution","pmids":["27865045"],"is_preprint":false},{"year":2017,"finding":"CRF upregulates CK8 expression in HT29 intestinal epithelial cells, and CK8 mediates CRF-induced activation of RhoA, actin remodeling, and downregulation of the tight junction protein ZO-1, contributing to increased intestinal permeability. CK8 silencing did not block CRF-induced downregulation of claudin-1 or occludin, indicating those effects are CK8-independent.","method":"shRNA knockdown of CK8 in HT29 cells, FITC-dextran permeability assay, RhoA activity immunoprecipitation, Western blot for tight junction proteins, transmission electron microscopy","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with specific molecular readouts (RhoA, ZO-1, actin) and functional permeability assay; also defines negative results (claudin-1/occludin not CK8-dependent); single lab","pmids":["29179184"],"is_preprint":false},{"year":2020,"finding":"KRT8 mediates primordial germ cell (PGC) migration in human pluripotent stem cell-derived DDX4ec PGCLCs; KRT8 is highly expressed in these cells and plays a crucial role in their migration, as demonstrated by functional experiments.","method":"hPSC differentiation to PGCLCs, KRT8 expression analysis, functional migration assays","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional migration assay with KRT8 manipulation, single lab, limited mechanistic detail in abstract","pmids":["33490911"],"is_preprint":false},{"year":2024,"finding":"TEAD4 regulates Krt8 expression in mouse preimplantation embryos; TEAD4 knockout (via base editing) reduces Krt8 expression and causes developmental arrest at the morula stage, with a dramatic decrease in nuclear YAP in outside cells, suggesting TEAD4 directly regulates Hippo signaling via Krt8 and YAP. This regulation is not conserved in cattle.","method":"Base editing TEAD4 knockout in mouse embryos, RNA-seq, immunofluorescence for nuclear YAP, comparison with bovine TEAD4-depleted embryos","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with RNA-seq and specific protein readouts (YAP localization), cross-species comparison adds context; single lab","pmids":["38206180"],"is_preprint":false}],"current_model":"KRT8 (keratin 8) is a type II intermediate filament protein that obligatorily heterodimerizes with the type I keratin K18 to form tetrameric units that rapidly polymerize into filaments; its assembly dynamics, filament mechanics, and protein-protein interactions (with K18, plectin, and PKC/PKN kinases) are well characterized in vitro and in vivo. KRT8 organizes the apical domain of simple polarized epithelia, facilitates mitochondrial fission-mediated mitophagy through physical interaction with plectin, is phosphorylated by PKC and PKN1/2 (at Ser43) in response to mechanical stress leading to filament disassembly, and its mRNA stability is enhanced by NAT10-catalyzed ac4C modification; ectopic induction of K8/K18 in cardiomyocytes via TNF-α/NF-κB confers cardioprotection by maintaining intercalated disc and mitochondrial integrity."},"narrative":{"mechanistic_narrative":"KRT8 (keratin 8) is a type II intermediate filament protein that obligatorily partners with type I keratins to build the simple-epithelial cytoskeleton: K8 forms homogeneous tetrameric starter units with K18 that polymerize into filaments several-fold faster than vimentin or desmin, with assembly driven by head-to-tail dimer-dimer contacts at the ends of the central rod that become conformationally protected upon filament formation [PMID:22085677, PMID:26434626]. In vivo, this K8-containing filament network organizes the apical domain of simple polarized epithelia, where its loss in enterocytes mislocalizes apical membrane proteins, syntaxin 3, and γ-tubulin and disorganizes microtubules [PMID:11171325]. Network mechanics are tuned by ions and the cytolinker plectin, which crosslinks filaments and stiffens the cytoskeleton [PMID:27489177]; through a direct physical interaction with plectin, KRT8 also associates with mitochondria and supports mitochondrial fission-mediated mitophagy under oxidative stress, limiting accumulation of damaged mitochondria and necrotic death [PMID:33783309]. KRT8 function is gated by phosphorylation: protein kinase C, ERK1/2, and the RHOA-PKN axis phosphorylate KRT8 (PKN at Ser43) in response to mechanical or oxidative stress, driving filament disassembly, impairing autophagosome initiation and autophagosome-lysosome fusion, and disrupting the plectin-mitochondria association [PMID:1283312, PMID:28045574, PMID:32022439, PMID:36897022, PMID:24166186]. Phospho-KRT8 produced by mechanical load impedes Golgi-resident RAB33B trafficking and suppresses autophagy, and conditional Krt8 deletion aggravates load-induced intervertebral disc degeneration while overexpression is protective [PMID:36897022]. KRT8 abundance is further controlled at the mRNA level by NAT10-catalyzed ac4C modification [PMID:38922788] and transcriptionally by TEAD4 during preimplantation development, where it links to Hippo/YAP signaling [PMID:38206180]. Beyond simple epithelia, ectopic TNF-α/NF-κB-driven induction of K8/K18 in cardiomyocytes localizes to intercalated discs and confers cardioprotection by maintaining disc and mitochondrial integrity [PMID:26280121], and elevated/stabilized KRT8 promotes EMT, migration, and tumorigenesis in multiple cancer contexts [PMID:22701666, PMID:9152022].","teleology":[{"year":1992,"claim":"Established that KRT8 is a regulated phosphoprotein in vivo, identifying it as a direct PKC substrate and opening the question of how phosphorylation controls filament behavior.","evidence":"Metabolic phosphorylation labeling with TPA/PKC manipulation in primary mouse hepatocytes","pmids":["1283312"],"confidence":"Medium","gaps":["Specific phosphorylation site not mapped","Functional consequence for filament assembly not assessed","Single pharmacological approach"]},{"year":1997,"claim":"Showed that K8 expression alone can nucleate keratin filaments with type I partners and that K8 versus K18 have opposing effects on tumor behavior, framing K8 as pro-migratory and pro-tumorigenic.","evidence":"Stable K8/K18 transfection into keratin-negative pancreatic adenocarcinoma cells with motility, soft-agar, and syngeneic tumor assays","pmids":["9152022"],"confidence":"Medium","gaps":["Molecular basis of K8 pro-motility effect unknown","Single cell line/lab","Does not separate filament-dependent from filament-independent effects"]},{"year":2001,"claim":"Demonstrated a cell-biological function for K8-containing IFs in vivo: organizing the apical domain and microtubule/MTOC positioning in simple polarized epithelia.","evidence":"CK8-knockout mouse intestinal enterocytes with immunofluorescence of apical markers, syntaxin 3, and γ-tubulin","pmids":["11171325"],"confidence":"High","gaps":["Molecular mechanism linking keratin to apical protein delivery unresolved","Direct interactors mediating MTOC positioning not identified"]},{"year":2011,"claim":"Resolved the biophysical assembly pathway, establishing K8/K18 tetramers as rapid starter units and quantifying filament mechanics relative to other IFs.","evidence":"Recombinant reconstitution with analytical ultracentrifugation, sedimentation equilibrium, EM, and assembly kinetics","pmids":["22085677"],"confidence":"High","gaps":["In vitro system lacks cellular crosslinkers and regulatory phosphorylation","Does not address higher-order network organization in cells"]},{"year":2011,"claim":"Linked KRT8 genetically to CFTR-mediated chloride secretion and CF severity, implying a role in apical CFTR targeting.","evidence":"Candidate gene SNP association study in stratified F508del-CFTR cystic fibrosis patients","pmids":["21548936"],"confidence":"Low","gaps":["Genetic association only with no direct molecular/cellular experiment","Causal mechanism of CFTR targeting not demonstrated"]},{"year":2012,"claim":"Connected KRT8 phosphorylation status to filament stability and oncogenic behavior through a PKP3-PRL3 phosphatase circuit.","evidence":"PKP3/K8 shRNA knockdown and double-knockdown rescue in HCT116 with migration, soft-agar, and xenograft assays","pmids":["22701666"],"confidence":"Medium","gaps":["Direct dephosphorylation of K8 by PRL3 not shown","Specific phosphosite not defined","Single lab"]},{"year":2013,"claim":"Established mechanical load as a physiological trigger for PKC-mediated KRT8 phosphorylation and disassembly, corroborated in human degenerative disc tissue.","evidence":"In vitro compressive loading of nucleus pulposus cells with PKC inhibition and human IDD tissue analysis","pmids":["24166186"],"confidence":"Medium","gaps":["Downstream consequence of disassembly not defined here","Phosphosite not mapped","Single lab"]},{"year":2015,"claim":"Refined the structural model by identifying which rod-end consensus motifs lock in during filament assembly and distinguishing K8 (self-oligomerizing) from K18 (monomeric) behavior.","evidence":"HDX-MS of recombinant K8/K18 across assembly states","pmids":["26434626"],"confidence":"High","gaps":["No atomic-resolution structure","Dynamics measured in vitro without regulatory modifications"]},{"year":2015,"claim":"Revealed a cardioprotective, organelle-maintenance role for ectopically induced K8/K18 via TNF-α/NF-κB, expanding KRT8 function beyond epithelia.","evidence":"Desmin-KO and TNF-α overexpression mouse models with aortic constriction, EM, and mitochondrial function assays","pmids":["26280121"],"confidence":"High","gaps":["Molecular mechanism by which K8/K18 preserves intercalated disc/mitochondria not defined","Relevance to non-desmin-deficient hearts unclear"]},{"year":2017,"claim":"Defined opposing roles of KRT8 abundance versus phosphorylation in stress: autophagy-promoted KRT8 is cytoprotective while ERK1/2 phosphorylation drives pathological EMT.","evidence":"Autophagy and MAPK inhibition plus siRNA in RPE cells under oxidative stress","pmids":["28045574"],"confidence":"Medium","gaps":["Specific ERK phosphosite not mapped","Mechanism coupling KRT8 to EMT program not detailed","Single lab"]},{"year":2017,"claim":"Placed KRT8 upstream of Integrinβ1-FAK and TGFβ/Smad signaling to promote EMT in gastric cancer.","evidence":"KRT8 overexpression/siRNA in gastric cancer lines with Western blot pathway analysis and migration assays","pmids":["27865045"],"confidence":"Low","gaps":["Pathway placement by Western blot without reconstitution","Direct physical link to Integrinβ1-FAK not shown","Single lab"]},{"year":2017,"claim":"Implicated KRT8 in CRF-driven intestinal barrier dysfunction through RhoA activation, actin remodeling, and ZO-1 downregulation.","evidence":"CK8 shRNA knockdown in HT29 cells with permeability, RhoA activity, and tight junction readouts","pmids":["29179184"],"confidence":"Medium","gaps":["Mechanism linking keratin to RhoA activation unknown","Effects shown to be specific (claudin-1/occludin independent) but not generalized","Single lab"]},{"year":2020,"claim":"Mechanistically tied KRT8 phosphorylation to impaired autophagosome-lysosome fusion during EMT, with disease relevance to proliferative vitreoretinopathy.","evidence":"Site-directed phosphosite mutagenesis and siRNA in RPE cells plus phospho-KRT8 detection in patient membranes","pmids":["32022439"],"confidence":"Medium","gaps":["Molecular step in fusion machinery affected not identified","Single lab"]},{"year":2020,"claim":"Extended KRT8 function to developmental cell migration in human PGC-like cells.","evidence":"hPSC-derived PGCLC differentiation with KRT8 manipulation and migration assays","pmids":["33490911"],"confidence":"Low","gaps":["Limited mechanistic detail","Single lab","Direct effectors of migration not defined"]},{"year":2021,"claim":"Identified the KRT8-plectin-mitochondria axis as the structural basis for KRT8-supported mitophagy, and showed phosphorylation disrupts it.","evidence":"Co-IP of KRT8-PLEC, mitochondrial imaging, mitophagy flux, and knockdown in oxidatively stressed RPE cells","pmids":["33783309"],"confidence":"Medium","gaps":["Co-IP without reciprocal/structural validation of the interaction interface","How keratin promotes mitochondrial fission mechanistically unclear","Single lab"]},{"year":2023,"claim":"Delivered the most complete mechanical-stress circuit: RHOA-PKN phosphorylates KRT8 at Ser43 to block RAB33B trafficking and autophagosome initiation, driving disc degeneration, validated by in vivo loss- and gain-of-function.","evidence":"Conditional Krt8 KO and AAV overexpression mice, Ser43 phosphosite assays, RAB33B trafficking, and IDD models","pmids":["36897022"],"confidence":"High","gaps":["How phospho-KRT8 physically impedes RAB33B trafficking not resolved","Generality of Ser43 axis to other tissues untested"]},{"year":2024,"claim":"Showed KRT8 abundance is post-transcriptionally controlled by NAT10-catalyzed ac4C mRNA modification, coupling this regulation to EMT and migration in prostate cancer.","evidence":"NAT10 knockdown/overexpression, acRIP-seq, and mRNA stability assays in prostate cancer cells","pmids":["38922788"],"confidence":"Medium","gaps":["ac4C site on KRT8 mRNA not pinpointed","Single lab"]},{"year":2024,"claim":"Identified transcriptional control of Krt8 by TEAD4 in mouse preimplantation embryos, linking it to Hippo/YAP signaling and morula-stage development.","evidence":"Base-editing TEAD4 knockout in mouse embryos with RNA-seq and nuclear YAP immunofluorescence, cross-species comparison","pmids":["38206180"],"confidence":"Medium","gaps":["Direct TEAD4 binding to Krt8 regulatory region not shown","Mechanistic role of Krt8 in YAP localization unresolved","Not conserved in cattle"]},{"year":null,"claim":"How the multiple stress-activated kinases (PKC, ERK1/2, PKN) converge on distinct KRT8 phosphosites to selectively control filament disassembly, plectin-mitochondria coupling, and autophagy flux in a tissue-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Full phosphosite map and kinase-site specificity incomplete","Structural basis of KRT8-plectin and phospho-KRT8-RAB33B effects unknown","Unifying model across epithelia, cardiomyocytes, and nucleus pulposus lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,8,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,9,10]}],"complexes":[],"partners":["KRT18","PLEC","KRT19"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05787","full_name":"Keratin, type II cytoskeletal 8","aliases":["Cytokeratin-8","CK-8","Keratin-8","K8","Type-II keratin Kb8"],"length_aa":483,"mass_kda":53.7,"function":"Required for the formation of KRT8/KRT18 filaments that are involved in ARHGEF40-mediated actin stress fiber formation and tensional force-induced stress fiber formation and reinforcement (PubMed:26823019). Together with KRT19, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle","subcellular_location":"Cytoplasm; Nucleus, nucleoplasm; Nucleus matrix; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P05787/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT8","classification":"Common Essential","n_dependent_lines":235,"n_total_lines":381,"dependency_fraction":0.6167979002624672},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT8","total_profiled":1310},"omim":[{"mim_id":"619770","title":"YDJC CHITOOLIGOSACCHARIDE DEACETYLASE HOMOLOG; YDJC","url":"https://www.omim.org/entry/619770"},{"mim_id":"612654","title":"TRICHOPLEIN; TCHP","url":"https://www.omim.org/entry/612654"},{"mim_id":"610018","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 40; ARHGEF40","url":"https://www.omim.org/entry/610018"},{"mim_id":"608218","title":"KERATIN 20, TYPE I; KRT20","url":"https://www.omim.org/entry/608218"},{"mim_id":"606841","title":"DEATH EFFECTOR DOMAIN-CONTAINING PROTEIN; DEDD","url":"https://www.omim.org/entry/606841"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":1281.6},{"tissue":"stomach 1","ntpm":768.4}],"url":"https://www.proteinatlas.org/search/KRT8"},"hgnc":{"alias_symbol":["CARD2","K8","CK8","CK-8","CYK8","K2C8","KO"],"prev_symbol":[]},"alphafold":{"accession":"P05787","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05787","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05787-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05787-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT8","jax_strain_url":"https://www.jax.org/strain/search?query=KRT8"},"sequence":{"accession":"P05787","fasta_url":"https://rest.uniprot.org/uniprotkb/P05787.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05787/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05787"}},"corpus_meta":[{"pmid":"32678092","id":"PMC_32678092","title":"Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung 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N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27213760","citation_count":12,"is_preprint":false},{"pmid":"34072918","id":"PMC_34072918","title":"Alleviation of LPS-Induced Inflammation and Septic Shock by Lactiplantibacillus plantarum K8 Lysates.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34072918","citation_count":12,"is_preprint":false},{"pmid":"1631798","id":"PMC_1631798","title":"Down-regulation of urokinase secretion from a human lymphoma cell line RC-K8 by dexamethasone without inducing plasminogen activator inhibitors.","date":"1992","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/1631798","citation_count":12,"is_preprint":false},{"pmid":"12788632","id":"PMC_12788632","title":"Lytic switch protein (ORF50) response element in the Kaposi's sarcoma-associated herpesvirus K8 promoter is located within but does not require a palindromic structure.","date":"2003","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/12788632","citation_count":12,"is_preprint":false},{"pmid":"9152022","id":"PMC_9152022","title":"Contrasting effects of K8 and K18 on stabilizing K19 expression, cell motility and tumorigenicity in the BSp73 adenocarcinoma.","date":"1997","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9152022","citation_count":11,"is_preprint":false},{"pmid":"33061604","id":"PMC_33061604","title":"CREB1 Suppresses Transcription of microRNA-186 to Promote Growth, Invasion and Epithelial-Mesenchymal Transition of Gastric Cancer Cells Through the KRT8/HIF-1α Axis.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33061604","citation_count":11,"is_preprint":false},{"pmid":"33490911","id":"PMC_33490911","title":"Human pluripotent stem cell-derived DDX4 and KRT-8 positive cells participate in ovarian follicle-like structure formation.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/33490911","citation_count":10,"is_preprint":false},{"pmid":"21232847","id":"PMC_21232847","title":"A rearranged EP300 gene in the human B-cell lymphoma cell line RC-K8 encodes a disabled transcriptional co-activator that contributes to cell growth and oncogenicity.","date":"2011","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/21232847","citation_count":10,"is_preprint":false},{"pmid":"29179184","id":"PMC_29179184","title":"Potential Regulatory Effects of Corticotropin-Releasing Factor on Tight Junction-Related Intestinal Epithelial Permeability are Partially Mediated by CK8 Upregulation.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29179184","citation_count":10,"is_preprint":false},{"pmid":"26434626","id":"PMC_26434626","title":"Analysis of distinct molecular assembly complexes of keratin K8 and K18 by hydrogen-deuterium exchange.","date":"2015","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/26434626","citation_count":10,"is_preprint":false},{"pmid":"7548228","id":"PMC_7548228","title":"Protein kinase activity-dependent inhibition of urokinase-type plasminogen activator gene transcription by cyclic AMP in human pre-B lymphoma cell line RC-K8.","date":"1995","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7548228","citation_count":10,"is_preprint":false},{"pmid":"24605136","id":"PMC_24605136","title":"Relationship of CK8/18 expression pattern to breast cancer immunohistochemical subtyping in Egyptian patients.","date":"2014","source":"Ecancermedicalscience","url":"https://pubmed.ncbi.nlm.nih.gov/24605136","citation_count":9,"is_preprint":false},{"pmid":"27489177","id":"PMC_27489177","title":"Both monovalent cations and plectin are potent modulators of mechanical properties of keratin K8/K18 networks.","date":"2016","source":"Soft matter","url":"https://pubmed.ncbi.nlm.nih.gov/27489177","citation_count":9,"is_preprint":false},{"pmid":"38206180","id":"PMC_38206180","title":"TEAD4 regulates KRT8 and YAP in preimplantation embryos in mice but not in cattle.","date":"2024","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38206180","citation_count":8,"is_preprint":false},{"pmid":"19843143","id":"PMC_19843143","title":"Cell blocks allow reliable evaluation of expression of basal (CK5/6) and luminal (CK8/18) cytokeratins and smooth muscle actin (SMA) in breast carcinoma.","date":"2009","source":"Cytopathology : official journal of the British Society for Clinical Cytology","url":"https://pubmed.ncbi.nlm.nih.gov/19843143","citation_count":7,"is_preprint":false},{"pmid":"37796128","id":"PMC_37796128","title":"Kaposi's sarcoma-associated herpesvirus glycoprotein K8.1 is critical for infection in a cell-specific manner and functions at the attachment step on keratinocytes.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37796128","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53609,"output_tokens":5103,"usd":0.118686,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13391,"output_tokens":5551,"usd":0.102865,"stage2_stop_reason":"end_turn"},"total_usd":0.221551,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"K8 and K18 form homogeneous tetrameric complexes when mixed and renatured together (confirmed by analytical ultracentrifugation and sedimentation equilibrium), and these tetramers serve as starter units for rapid filament assembly; K8/K18 filaments assemble several times faster than vimentin and desmin, with a persistence length of ~300 nm that increases to ~480 nm upon addition of MgCl2.\",\n      \"method\": \"Recombinant protein reconstitution, analytical ultracentrifugation, sedimentation equilibrium centrifugation, electron microscopy, in vitro filament assembly kinetics\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro from recombinant proteins with multiple orthogonal biophysical methods (AUC, sedimentation equilibrium, EM, length profiling)\",\n      \"pmids\": [\"22085677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Hydrogen-deuterium exchange mass spectrometry of K8/K18 complexes revealed that IF-consensus motifs at the ends of the central α-helical rod segment (mediating head-to-tail dimer-dimer interaction) become distinctly more protected upon filament formation, while some coiled-coil regions remain dynamic; K8 forms dimers/tetramers alone whereas K18 is monomeric alone.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) of recombinant K8/K18 at various assembly states\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — HDX-MS is a direct structural/dynamics method applied to multiple assembly states with rigorous controls\",\n      \"pmids\": [\"26434626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"KRT8 (CK8) is phosphorylated by protein kinase C (PKC) in primary hepatocytes; TPA (a PKC activator) transiently increases CK8 phosphorylation within 15 min, an effect abolished after PKC down-regulation, identifying CK8 as an in vivo PKC substrate. CK18 phosphorylation was not increased by TPA under the same conditions.\",\n      \"method\": \"Metabolic phosphorylation labeling, TPA/PKC pharmacological manipulation in primary mouse hepatocytes, indirect immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with PKC activator/down-regulation plus morphological readout, single lab\",\n      \"pmids\": [\"1283312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In CK8-null mouse intestinal villus enterocytes (the only cell type completely lacking IFs), apical membrane proteins (alkaline phosphatase, sucrase-isomaltase, CFTR) were lost progressively along the villus, syntaxin 3 was absent, and γ-tubulin was mislocalized from its normal sub-apical position, with disorganized microtubules — establishing a role for KRT8-containing intermediate filaments in organizing the apical domain of simple polarized epithelia.\",\n      \"method\": \"CK8-knockout mouse model, immunofluorescence localization of apical markers and cytoskeletal components in intestinal epithelia\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple specific molecular readouts (apical proteins, syntaxin 3, γ-tubulin, microtubules) in vivo\",\n      \"pmids\": [\"11171325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TNF-α induces ectopic expression of K8 and K18 in cardiomyocytes via NF-κB signaling; in desmin-deficient mice, the resulting K8/K18 network localizes primarily at intercalated discs and confers cardioprotection by maintaining normal intercalated disc structure and mitochondrial integrity and function. Loss of the K8/K18 network led to maladaptive cardiac phenotype after pressure overload.\",\n      \"method\": \"Genetic (desmin-KO, TNF-α overexpression) mouse models, NF-κB pathway analysis, transverse aortic constriction, electron microscopy, mitochondrial function assays, immunofluorescence\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models, loss-of-function (K8/K18 network ablation), gain-of-function (ectopic induction), and mechanistic link to NF-κB with functional cardiac readouts\",\n      \"pmids\": [\"26280121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of plakophilin3 (PKP3) leads to increased PRL3 phosphatase levels, which decreases phosphorylation of K8, stabilizing K8 filaments and increasing K8 protein levels; stabilized K8 promotes cell migration, lamellipodia formation, colony formation in soft agar, and tumorigenesis/metastasis in nude mice. K8 knockdown in the PKP3-knockdown background reverses these phenotypes.\",\n      \"method\": \"shRNA knockdown of PKP3 and K8 in HCT116 cells, Western blotting for K8 phosphorylation and PRL3, wound-healing/migration assays, soft agar colony formation, nude mouse xenografts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double knockdown rescue), multiple functional readouts, single lab\",\n      \"pmids\": [\"22701666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In retinal pigment epithelial (RPE) cells under oxidative stress, KRT8 upregulation (promoted by autophagy) is cytoprotective, whereas phosphorylation of KRT8 by MAPK1/ERK2 and MAPK3/ERK1 drives pathological epithelial-mesenchymal transition (EMT). Inhibition of autophagy further promotes EMT, which is reversible by MAPK inhibition.\",\n      \"method\": \"Autophagy inhibition, MAPK pharmacological inhibition, siRNA knockdown, Western blotting, immunofluorescence in RPE cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic interventions, identified specific kinases (ERK1/2), single lab\",\n      \"pmids\": [\"28045574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KRT8 phosphorylation (at critical phosphorylated site) impairs autophagosome-lysosome fusion; mutagenesis of the phosphorylation site or KRT8 knockdown causes autophagy impairment in RPE cells undergoing TGF-β2-induced EMT, and phosphorylated KRT8 is detected in epiretinal/subretinal membranes of PVR patients.\",\n      \"method\": \"Site-directed mutagenesis of KRT8 phosphorylation site, siRNA knockdown, pharmacological autophagy inhibition, Western blot, immunofluorescence in RPE cells and patient membranes\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation site with specific functional readout (autophagosome-lysosome fusion), single lab\",\n      \"pmids\": [\"32022439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KRT8 physically interacts with the cytolinker protein PLEC (plectin) and through this interaction associates with mitochondria; this KRT8-PLEC association facilitates mitochondrial fission-mediated mitophagy in RPE cells under oxidative stress, suppressing accumulation of damaged mitochondria and necrotic cell death. KRT8 phosphorylation under oxidative stress diminishes the PLEC-mitochondria-KRT8 association.\",\n      \"method\": \"Co-immunoprecipitation (KRT8-PLEC interaction), mitochondrial morphology imaging, mitophagy flux assays, KRT8/PLEC knockdown, oxidative stress model in RPE cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, KO/KD with specific mitophagy and cell-death readouts, single lab\",\n      \"pmids\": [\"33783309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Excessive mechanical load activates RHOA-PKN (protein kinase N), which phosphorylates KRT8 on Ser43; this phosphorylation impedes trafficking of Golgi-resident RAB33B, suppresses autophagosome initiation, and contributes to intervertebral disc degeneration (IDD). Conditional knockout of Krt8 in nucleus pulposus aggravates load-induced IDD in vivo, while KRT8 overexpression confers resistance. Knockdown of PKN1/PKN2 at early IDD stage ameliorates degeneration.\",\n      \"method\": \"Conditional KO mouse, AAV-mediated KRT8 overexpression, site-specific phosphorylation assays (Ser43), RHOA-PKN pathway analysis, RAB33B trafficking assays, in vivo IDD models (lumbar instability, tail compression)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identified specific phosphorylation site (Ser43), identified writer kinase (PKN), downstream effector (RAB33B/autophagosome initiation), validated in vivo KO and OE with functional disc degeneration readouts\",\n      \"pmids\": [\"36897022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Compressive mechanical loads applied to nucleus pulposus cells cause time- and dose-dependent phosphorylation and disassembly of CK8, mediated by activation of protein kinase C (PKC). In human IDD tissue, CK8 expression is decreased with increased phosphorylation.\",\n      \"method\": \"In vitro compressive loading of NP cells, PKC inhibitor studies, Western blotting for phospho-CK8, human IDD tissue analysis\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological PKC inhibition establishes PKC as mediator, dose/time dependence of mechanical loading, corroborated by human tissue; single lab\",\n      \"pmids\": [\"24166186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Transfection of K8 into a vimentin-expressing pancreatic adenocarcinoma (no endogenous keratins) stabilized endogenous K19 and formed K8/K19 filaments; K8 expression increased cell motility and tumor growth, contrasting with K18 (which suppressed tumorigenicity). K18 required co-expression with K8 for stabilization.\",\n      \"method\": \"Stable transfection of K8 and K18 into BSp73 adenocarcinoma cells, soft agar growth assays, motility assays, syngeneic tumor formation in animals\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function transfection with multiple functional readouts (migration, tumor growth), single lab\",\n      \"pmids\": [\"9152022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vitro, potassium ions induce bundling of K8/K18 filaments and significantly stiffen the network, while the cytolinker plectin crosslinks filaments at intersection points without bundle formation but increases network rigidity at concentrations above ~20% of cellular plectin levels. In situ, plectin downregulation to ~10% significantly decreases cell stiffness of IF-containing cytoskeletons.\",\n      \"method\": \"In vitro K8/K18 network assembly with potassium ions and recombinant plectin, microrheology, atomic force microscopy on detergent-extracted A431 cells with plectin siRNA knockdown\",\n      \"journal\": \"Soft matter\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstituted in vitro networks plus in situ functional mechanics, single lab with two orthogonal methods\",\n      \"pmids\": [\"27489177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KRT8 (but not KRT18) genetic variants are associated with CFTR-mediated residual chloride secretion in F508del-CFTR homozygous cystic fibrosis patients and with CF disease severity, suggesting that K8/K18 heterodimeric intermediate filaments are required for proper CFTR targeting to the apical membrane in epithelial cells.\",\n      \"method\": \"Candidate gene association study with SNP haplotyping in contrasting CF patient subpopulations stratified by disease severity and CFTR chloride secretion\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic association only; no direct molecular or cellular experiment establishing the mechanism; functional inference is indirect\",\n      \"pmids\": [\"21548936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 (N-acetyltransferase 10) stabilizes KRT8 mRNA by catalyzing N4-acetylcytidine (ac4C) modification of KRT8 mRNA, increasing KRT8 protein levels and thereby promoting epithelial-mesenchymal transition and cell migration in prostate cancer cells.\",\n      \"method\": \"NAT10 knockdown/overexpression, acRIP-seq (ac4C RNA immunoprecipitation sequencing) to identify KRT8 mRNA as NAT10 target, mRNA stability assays, EMT marker analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C modification of KRT8 mRNA identified by acRIP-seq with functional validation (mRNA stability, EMT), single lab\",\n      \"pmids\": [\"38922788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KRT8 overexpression in gastric cancer cells activates Integrinβ1-FAK-induced EMT signaling, and KRT8 overexpression increases p-Smad2/3 levels, placing KRT8 upstream of TGFβ-dependent signaling events and EMT.\",\n      \"method\": \"KRT8 overexpression and siRNA knockdown in gastric cancer cell lines, Western blotting for Integrinβ1-FAK and p-Smad2/3, migration assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by Western blot without direct mechanistic reconstitution\",\n      \"pmids\": [\"27865045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRF upregulates CK8 expression in HT29 intestinal epithelial cells, and CK8 mediates CRF-induced activation of RhoA, actin remodeling, and downregulation of the tight junction protein ZO-1, contributing to increased intestinal permeability. CK8 silencing did not block CRF-induced downregulation of claudin-1 or occludin, indicating those effects are CK8-independent.\",\n      \"method\": \"shRNA knockdown of CK8 in HT29 cells, FITC-dextran permeability assay, RhoA activity immunoprecipitation, Western blot for tight junction proteins, transmission electron microscopy\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with specific molecular readouts (RhoA, ZO-1, actin) and functional permeability assay; also defines negative results (claudin-1/occludin not CK8-dependent); single lab\",\n      \"pmids\": [\"29179184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KRT8 mediates primordial germ cell (PGC) migration in human pluripotent stem cell-derived DDX4ec PGCLCs; KRT8 is highly expressed in these cells and plays a crucial role in their migration, as demonstrated by functional experiments.\",\n      \"method\": \"hPSC differentiation to PGCLCs, KRT8 expression analysis, functional migration assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional migration assay with KRT8 manipulation, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"33490911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD4 regulates Krt8 expression in mouse preimplantation embryos; TEAD4 knockout (via base editing) reduces Krt8 expression and causes developmental arrest at the morula stage, with a dramatic decrease in nuclear YAP in outside cells, suggesting TEAD4 directly regulates Hippo signaling via Krt8 and YAP. This regulation is not conserved in cattle.\",\n      \"method\": \"Base editing TEAD4 knockout in mouse embryos, RNA-seq, immunofluorescence for nuclear YAP, comparison with bovine TEAD4-depleted embryos\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with RNA-seq and specific protein readouts (YAP localization), cross-species comparison adds context; single lab\",\n      \"pmids\": [\"38206180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT8 (keratin 8) is a type II intermediate filament protein that obligatorily heterodimerizes with the type I keratin K18 to form tetrameric units that rapidly polymerize into filaments; its assembly dynamics, filament mechanics, and protein-protein interactions (with K18, plectin, and PKC/PKN kinases) are well characterized in vitro and in vivo. KRT8 organizes the apical domain of simple polarized epithelia, facilitates mitochondrial fission-mediated mitophagy through physical interaction with plectin, is phosphorylated by PKC and PKN1/2 (at Ser43) in response to mechanical stress leading to filament disassembly, and its mRNA stability is enhanced by NAT10-catalyzed ac4C modification; ectopic induction of K8/K18 in cardiomyocytes via TNF-α/NF-κB confers cardioprotection by maintaining intercalated disc and mitochondrial integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT8 (keratin 8) is a type II intermediate filament protein that obligatorily partners with type I keratins to build the simple-epithelial cytoskeleton: K8 forms homogeneous tetrameric starter units with K18 that polymerize into filaments several-fold faster than vimentin or desmin, with assembly driven by head-to-tail dimer-dimer contacts at the ends of the central rod that become conformationally protected upon filament formation [#0, #1]. In vivo, this K8-containing filament network organizes the apical domain of simple polarized epithelia, where its loss in enterocytes mislocalizes apical membrane proteins, syntaxin 3, and γ-tubulin and disorganizes microtubules [#3]. Network mechanics are tuned by ions and the cytolinker plectin, which crosslinks filaments and stiffens the cytoskeleton [#12]; through a direct physical interaction with plectin, KRT8 also associates with mitochondria and supports mitochondrial fission-mediated mitophagy under oxidative stress, limiting accumulation of damaged mitochondria and necrotic death [#8]. KRT8 function is gated by phosphorylation: protein kinase C, ERK1/2, and the RHOA-PKN axis phosphorylate KRT8 (PKN at Ser43) in response to mechanical or oxidative stress, driving filament disassembly, impairing autophagosome initiation and autophagosome-lysosome fusion, and disrupting the plectin-mitochondria association [#2, #6, #7, #9, #10]. Phospho-KRT8 produced by mechanical load impedes Golgi-resident RAB33B trafficking and suppresses autophagy, and conditional Krt8 deletion aggravates load-induced intervertebral disc degeneration while overexpression is protective [#9]. KRT8 abundance is further controlled at the mRNA level by NAT10-catalyzed ac4C modification [#14] and transcriptionally by TEAD4 during preimplantation development, where it links to Hippo/YAP signaling [#18]. Beyond simple epithelia, ectopic TNF-α/NF-κB-driven induction of K8/K18 in cardiomyocytes localizes to intercalated discs and confers cardioprotection by maintaining disc and mitochondrial integrity [#4], and elevated/stabilized KRT8 promotes EMT, migration, and tumorigenesis in multiple cancer contexts [#5, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that KRT8 is a regulated phosphoprotein in vivo, identifying it as a direct PKC substrate and opening the question of how phosphorylation controls filament behavior.\",\n      \"evidence\": \"Metabolic phosphorylation labeling with TPA/PKC manipulation in primary mouse hepatocytes\",\n      \"pmids\": [\"1283312\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Specific phosphorylation site not mapped\", \"Functional consequence for filament assembly not assessed\", \"Single pharmacological approach\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that K8 expression alone can nucleate keratin filaments with type I partners and that K8 versus K18 have opposing effects on tumor behavior, framing K8 as pro-migratory and pro-tumorigenic.\",\n      \"evidence\": \"Stable K8/K18 transfection into keratin-negative pancreatic adenocarcinoma cells with motility, soft-agar, and syngeneic tumor assays\",\n      \"pmids\": [\"9152022\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of K8 pro-motility effect unknown\", \"Single cell line/lab\", \"Does not separate filament-dependent from filament-independent effects\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated a cell-biological function for K8-containing IFs in vivo: organizing the apical domain and microtubule/MTOC positioning in simple polarized epithelia.\",\n      \"evidence\": \"CK8-knockout mouse intestinal enterocytes with immunofluorescence of apical markers, syntaxin 3, and γ-tubulin\",\n      \"pmids\": [\"11171325\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism linking keratin to apical protein delivery unresolved\", \"Direct interactors mediating MTOC positioning not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the biophysical assembly pathway, establishing K8/K18 tetramers as rapid starter units and quantifying filament mechanics relative to other IFs.\",\n      \"evidence\": \"Recombinant reconstitution with analytical ultracentrifugation, sedimentation equilibrium, EM, and assembly kinetics\",\n      \"pmids\": [\"22085677\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vitro system lacks cellular crosslinkers and regulatory phosphorylation\", \"Does not address higher-order network organization in cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked KRT8 genetically to CFTR-mediated chloride secretion and CF severity, implying a role in apical CFTR targeting.\",\n      \"evidence\": \"Candidate gene SNP association study in stratified F508del-CFTR cystic fibrosis patients\",\n      \"pmids\": [\"21548936\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Genetic association only with no direct molecular/cellular experiment\", \"Causal mechanism of CFTR targeting not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected KRT8 phosphorylation status to filament stability and oncogenic behavior through a PKP3-PRL3 phosphatase circuit.\",\n      \"evidence\": \"PKP3/K8 shRNA knockdown and double-knockdown rescue in HCT116 with migration, soft-agar, and xenograft assays\",\n      \"pmids\": [\"22701666\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct dephosphorylation of K8 by PRL3 not shown\", \"Specific phosphosite not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established mechanical load as a physiological trigger for PKC-mediated KRT8 phosphorylation and disassembly, corroborated in human degenerative disc tissue.\",\n      \"evidence\": \"In vitro compressive loading of nucleus pulposus cells with PKC inhibition and human IDD tissue analysis\",\n      \"pmids\": [\"24166186\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream consequence of disassembly not defined here\", \"Phosphosite not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the structural model by identifying which rod-end consensus motifs lock in during filament assembly and distinguishing K8 (self-oligomerizing) from K18 (monomeric) behavior.\",\n      \"evidence\": \"HDX-MS of recombinant K8/K18 across assembly states\",\n      \"pmids\": [\"26434626\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No atomic-resolution structure\", \"Dynamics measured in vitro without regulatory modifications\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a cardioprotective, organelle-maintenance role for ectopically induced K8/K18 via TNF-α/NF-κB, expanding KRT8 function beyond epithelia.\",\n      \"evidence\": \"Desmin-KO and TNF-α overexpression mouse models with aortic constriction, EM, and mitochondrial function assays\",\n      \"pmids\": [\"26280121\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism by which K8/K18 preserves intercalated disc/mitochondria not defined\", \"Relevance to non-desmin-deficient hearts unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined opposing roles of KRT8 abundance versus phosphorylation in stress: autophagy-promoted KRT8 is cytoprotective while ERK1/2 phosphorylation drives pathological EMT.\",\n      \"evidence\": \"Autophagy and MAPK inhibition plus siRNA in RPE cells under oxidative stress\",\n      \"pmids\": [\"28045574\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Specific ERK phosphosite not mapped\", \"Mechanism coupling KRT8 to EMT program not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed KRT8 upstream of Integrinβ1-FAK and TGFβ/Smad signaling to promote EMT in gastric cancer.\",\n      \"evidence\": \"KRT8 overexpression/siRNA in gastric cancer lines with Western blot pathway analysis and migration assays\",\n      \"pmids\": [\"27865045\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Pathway placement by Western blot without reconstitution\", \"Direct physical link to Integrinβ1-FAK not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated KRT8 in CRF-driven intestinal barrier dysfunction through RhoA activation, actin remodeling, and ZO-1 downregulation.\",\n      \"evidence\": \"CK8 shRNA knockdown in HT29 cells with permeability, RhoA activity, and tight junction readouts\",\n      \"pmids\": [\"29179184\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking keratin to RhoA activation unknown\", \"Effects shown to be specific (claudin-1/occludin independent) but not generalized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistically tied KRT8 phosphorylation to impaired autophagosome-lysosome fusion during EMT, with disease relevance to proliferative vitreoretinopathy.\",\n      \"evidence\": \"Site-directed phosphosite mutagenesis and siRNA in RPE cells plus phospho-KRT8 detection in patient membranes\",\n      \"pmids\": [\"32022439\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular step in fusion machinery affected not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended KRT8 function to developmental cell migration in human PGC-like cells.\",\n      \"evidence\": \"hPSC-derived PGCLC differentiation with KRT8 manipulation and migration assays\",\n      \"pmids\": [\"33490911\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Limited mechanistic detail\", \"Single lab\", \"Direct effectors of migration not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the KRT8-plectin-mitochondria axis as the structural basis for KRT8-supported mitophagy, and showed phosphorylation disrupts it.\",\n      \"evidence\": \"Co-IP of KRT8-PLEC, mitochondrial imaging, mitophagy flux, and knockdown in oxidatively stressed RPE cells\",\n      \"pmids\": [\"33783309\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Co-IP without reciprocal/structural validation of the interaction interface\", \"How keratin promotes mitochondrial fission mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Delivered the most complete mechanical-stress circuit: RHOA-PKN phosphorylates KRT8 at Ser43 to block RAB33B trafficking and autophagosome initiation, driving disc degeneration, validated by in vivo loss- and gain-of-function.\",\n      \"evidence\": \"Conditional Krt8 KO and AAV overexpression mice, Ser43 phosphosite assays, RAB33B trafficking, and IDD models\",\n      \"pmids\": [\"36897022\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How phospho-KRT8 physically impedes RAB33B trafficking not resolved\", \"Generality of Ser43 axis to other tissues untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed KRT8 abundance is post-transcriptionally controlled by NAT10-catalyzed ac4C mRNA modification, coupling this regulation to EMT and migration in prostate cancer.\",\n      \"evidence\": \"NAT10 knockdown/overexpression, acRIP-seq, and mRNA stability assays in prostate cancer cells\",\n      \"pmids\": [\"38922788\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"ac4C site on KRT8 mRNA not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified transcriptional control of Krt8 by TEAD4 in mouse preimplantation embryos, linking it to Hippo/YAP signaling and morula-stage development.\",\n      \"evidence\": \"Base-editing TEAD4 knockout in mouse embryos with RNA-seq and nuclear YAP immunofluorescence, cross-species comparison\",\n      \"pmids\": [\"38206180\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct TEAD4 binding to Krt8 regulatory region not shown\", \"Mechanistic role of Krt8 in YAP localization unresolved\", \"Not conserved in cattle\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple stress-activated kinases (PKC, ERK1/2, PKN) converge on distinct KRT8 phosphosites to selectively control filament disassembly, plectin-mitochondria coupling, and autophagy flux in a tissue-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Full phosphosite map and kinase-site specificity incomplete\", \"Structural basis of KRT8-plectin and phospho-KRT8-RAB33B effects unknown\", \"Unifying model across epithelia, cardiomyocytes, and nucleus pulposus lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 8, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT18\", \"PLEC\", \"KRT19\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}