{"gene":"KRT8","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1982,"finding":"KRT8 (cytokeratin 8, a type II keratin) was catalogued as a component of simple epithelial intermediate filaments; it is expressed predominantly in simple and some stratified epithelia and forms obligate heteropolymeric filaments with type I keratin partners.","method":"Two-dimensional gel electrophoresis and immunological characterization of keratin proteins from normal epithelia, tumors, and cultured cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — foundational biochemical characterization, >5000 citations, multiple tissue types","pmids":["6186379"],"is_preprint":false},{"year":1992,"finding":"CK8 is preferentially phosphorylated over CK18 in primary hepatocytes; treatment with the protein kinase C activator TPA (phorbol ester) induces a transient, sustained increase in CK8 phosphorylation but not CK18 phosphorylation, identifying CK8 as an in vivo substrate of PKC. This phosphorylation was accompanied by cytokeratin aggregate formation in some cells but not wholesale filament disruption.","method":"Metabolic radiolabeling of primary mouse hepatocyte cultures treated with TPA, followed by immunoprecipitation and indirect immunofluorescence microscopy; PKC down-regulation experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — PKC activation/downregulation with biochemical readout, single lab","pmids":["1283312"],"is_preprint":false},{"year":1997,"finding":"In a pancreatic adenocarcinoma model (BSp73), expression of K8 alone stabilized endogenous K19 and enabled keratin filament formation (K8/K19 network), whereas K18 expression was unstable without K8 co-expression. K8/K19-expressing clones retained motility and tumorigenicity, while K18-expressing clones showed dramatically suppressed tumorigenicity and reduced soft-agar growth, indicating that K8 and K18 have opposing roles in regulating cell motility and tumor progression.","method":"Stable transfection of K8 and K18 individually and in combination into keratin-null adenocarcinoma cells; soft-agar colony assays, motility assays, syngeneic tumor injection","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain-of-function with multiple functional readouts, single lab","pmids":["9152022"],"is_preprint":false},{"year":2001,"finding":"In CK8-null mouse intestinal villus enterocytes (the only cell type lacking IF partners and thus without keratin filaments), apical membrane proteins (alkaline phosphatase, sucrase-isomaltase, CFTR) were progressively lost along the villus, syntaxin 3 was absent, and γ-tubulin mislocalized from its normal sub-apical position with disorganized microtubules. This establishes that the KRT8-based intermediate filament network is required for maintaining the apical membrane domain organization and microtubule anchoring in simple polarized epithelia.","method":"Analysis of CK8-knockout mice; immunofluorescence localization of apical markers, syntaxin 3, γ-tubulin, and microtubules in intestinal epithelia and hepatocytes","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple orthogonal phenotypic readouts, mechanistic pathway placement","pmids":["11171325"],"is_preprint":false},{"year":2011,"finding":"Recombinant human K8 and K18 assemble into intermediate filaments through a defined pathway: K8 alone forms dimers to tetramers, K18 alone is monomeric, but equimolar K8/K18 mixtures renature as homogeneous tetrameric complexes. These tetramers are the starter units for filament assembly, which proceeds several times faster than vimentin or desmin. The persistence length of K8/K18 filaments is ~300 nm, increasing to ~480 nm with Mg²⁺, indicating Mg²⁺ stiffens the filament by affecting subunit interactions.","method":"Analytical ultracentrifugation (sedimentation velocity and equilibrium), electron microscopy of filaments assembled at various protein concentrations and time points, persistence length measurements","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal biophysical methods","pmids":["22085677"],"is_preprint":false},{"year":2012,"finding":"Loss of the desmosomal plaque protein plakophilin3 (PKP3) in HCT116 cells elevates PRL3 (phosphatase of regenerating liver 3) protein levels, which reduces phosphorylation of K8. The resulting stabilized, dephosphorylated K8 promotes increased cell migration, lamellipodia formation, soft-agar colony formation, and metastasis in nude mice. K8/PKP3 double knockdown reversed these phenotypes, placing K8 downstream of PRL3 in a dephosphorylation-dependent mechanism of tumor progression.","method":"shRNA knockdown of PKP3 and K8 individually and in combination; Western blotting for PRL3 and phospho-K8; wound-healing and lamellipodia assays; soft-agar colony formation; nude mouse tumorigenesis and metastasis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, genetic epistasis, single lab","pmids":["22701666"],"is_preprint":false},{"year":2013,"finding":"CK8 expression is down-regulated in human intervertebral disc degeneration (IDD) nucleus pulposus (NP) cells. Compressive mechanical loads applied to cultured NP cells cause CK8 phosphorylation and filament disassembly in a time- and magnitude-dependent manner. Protein kinase C (PKC) activation is a critical molecular mediator of compressive load-induced CK8 phosphorylation and downregulation.","method":"Western blotting and qRT-PCR of human NP tissue samples; in vitro NP cell compressive loading with pharmacological PKC pathway analysis","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — human tissue validation combined with mechanistic in vitro loading experiments, single lab","pmids":["24166186"],"is_preprint":false},{"year":2015,"finding":"TNF-α, acting via NF-κB, drives ectopic expression of keratin 8 (K8) and keratin 18 (K18) in cardiomyocytes of desmin-deficient mice. The ectopic K8/K18 network localizes predominantly to intercalated discs, maintains normal intercalated disc structure and mitochondrial integrity and function, and confers cardioprotection. Loss of the K8/K18 network in this context leads to a maladaptive cardiac phenotype after aortic constriction.","method":"Genetic heart failure mouse models (desmin-null and transverse aortic constriction); immunofluorescence and electron microscopy of intercalated discs; mitochondrial function assays; NF-κB reporter and conditional knockout approaches; human failing myocardium immunostaining","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models, orthogonal mechanistic readouts, replicated in human tissue, published in high-impact journal","pmids":["26280121"],"is_preprint":false},{"year":2015,"finding":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) of K8/K18 complexes mapped regions of differential structural dynamics at the tetramer versus filament stages. The IF-consensus motifs at the ends of the central α-helical rod domain, which mediate head-to-tail dimer-dimer interactions, become significantly more protected (less exchangeable) upon filament formation, providing direct structural evidence that these regions drive filament elongation. Homomeric K8 and K18 preparations showed distinct exchange patterns from the heterodimer, revealing partner-dependent stabilization.","method":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) of recombinant K8, K18, and K8/K18 complexes at multiple assembly states (monomer/dimer, tetramer, filament)","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 — structural method (HDX-MS) applied across multiple assembly states with functional interpretation","pmids":["26434626"],"is_preprint":false},{"year":2016,"finding":"Plectin crosslinks K8/K18 intermediate filament networks at filament intersection points without inducing bundle formation, and plectin-mediated crosslinking increases network rigidity when added at amounts above ~20% of the plectin present in cells. In contrast, potassium ions cause K8/K18 filament bundling that also significantly stiffens the network. In detergent-extracted epithelial cells, downregulation of plectin to ~10% of normal levels significantly decreased cytoskeletal stiffness, establishing plectin as a major modulator of K8/K18 network mechanics.","method":"In vitro reconstitution of K8/K18 networks with potassium ions or purified plectin; microrheology; atomic force microscopy of detergent-extracted A431 cells with plectin siRNA knockdown","journal":"Soft matter","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with orthogonal in situ validation, multiple biophysical methods","pmids":["27489177"],"is_preprint":false},{"year":2017,"finding":"KRT8 upregulation following autophagy induction provides a cytoprotective role in retinal pigment epithelium (RPE) cells under oxidative stress. However, phosphorylation of KRT8 (mediated by MAPK1/ERK2 and MAPK3/ERK1) promotes pathological epithelial-mesenchymal transition (EMT) of RPE cells. Inhibition of autophagy further promotes EMT, which can be reversed by MAPK inhibition, establishing a dual role for KRT8 in RPE pathophysiology dependent on its phosphorylation state.","method":"RPE cell culture with oxidative stress; pharmacological autophagy inhibition and activation; MAPK1/3 inhibitors; immunofluorescence and Western blotting for phospho-KRT8, EMT markers, and autophagy markers","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological interventions with defined pathway placement, single lab","pmids":["28045574"],"is_preprint":false},{"year":2017,"finding":"KRT8 overexpression in gastric cancer cells enhanced proliferation and migration, and was associated with integrin β1-FAK-induced epithelial-mesenchymal transition (EMT) in high-KRT8 cells. KRT8 overexpression increased p-SMAD2/3 levels, linking KRT8 to TGF-β-dependent signaling and EMT.","method":"KRT8 siRNA knockdown and overexpression in gastric cancer cell lines; proliferation and migration assays; Western blotting for EMT markers, integrin β1-FAK pathway components, and p-SMAD2/3","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 3 — functional cell biology with partial pathway placement, single lab","pmids":["27865045"],"is_preprint":false},{"year":2020,"finding":"A unique Krt8+ transitional stem cell state arises during alveolar regeneration from both airway and alveolar stem cell lineages converging after lung injury. These Krt8+ cells display squamous morphology, activation of p53 and NF-κB transcriptional programs, and features of cellular senescence. In human lung fibrosis, this Krt8+ transitional state aberrantly persists, establishing a distinct cell-cell communication network with mesenchyme and macrophages.","method":"Time-series single-cell RNA-seq of bleomycin-injured mouse lungs; lineage tracing; trajectory modeling; validation in multiple independent lung injury models and human fibrosis samples","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — lineage tracing plus scRNA-seq trajectory analysis, replicated across multiple models and human tissue","pmids":["32678092"],"is_preprint":false},{"year":2020,"finding":"KRT8 phosphorylation correlates with autophagy progression during TGF-β2-induced EMT in retinal pigment epithelial cells. Knockdown of KRT8 or mutagenesis of its critical phosphorylation site impairs autophagosome-lysosome fusion, demonstrating that phosphorylated KRT8 is required for completion of autophagic flux during EMT.","method":"siRNA knockdown and phospho-site mutagenesis of KRT8 in RPE cells; TGF-β2-induced EMT; Western blotting and immunofluorescence for autophagy markers and EMT markers; transwell migration assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of specific phosphorylation site with defined functional consequence, single lab","pmids":["32022439"],"is_preprint":false},{"year":2020,"finding":"Cisplatin upregulates KRT8 in cancer-associated fibroblasts (CAFs), and this KRT8 upregulation suppresses AKT signaling in CAFs, attenuating their ability to promote lung cancer cell migration and invasion. Stimulation of AKT activity (with SC79) reversed KRT8's inhibitory effect on migration, linking KRT8 to suppression of the AKT pathway in CAFs.","method":"KRT8 knockdown/overexpression in CAFs; co-culture with lung cancer cells; wound-healing and transwell invasion assays; Western blotting for AKT pathway; nude mouse tumor models","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic depth, CAF-specific context","pmids":["32280245"],"is_preprint":false},{"year":2020,"finding":"Analysis of zebrafish periderm enhancers identified a regulatory SNP near the KRT8/KRT18 locus at 12q13 that lies within a periderm enhancer controlling KRT18/KRT8 expression. Reporter assays and deletion analyses confirmed this SNP functionally regulates KRT8/KRT18 expression in periderm cells and is associated with non-syndromic orofacial clefting risk.","method":"ATAC-seq on zebrafish periderm and human oral epithelium; gapped-kmer SVM classifiers; reporter assays; CRISPR deletion analysis in zebrafish","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — ATAC-seq plus functional reporter and deletion validation, relevant to KRT8 transcriptional regulation","pmids":["32031521"],"is_preprint":false},{"year":2021,"finding":"KRT8 physically interacts with the cytolinker protein PLEC (plectin) to tether mitochondria and facilitate mitochondrial fission-mediated mitophagy in RPE cells under oxidative stress. When KRT8 is phosphorylated under oxidative stress conditions, the KRT8-PLEC association is disrupted, impairing mitophagy and leading to accumulation of damaged mitochondria and necrotic cell death.","method":"Co-immunoprecipitation to identify KRT8-PLEC interaction; siRNA knockdown of KRT8 and PLEC; mitochondrial morphology and membrane potential assays; mitophagy flux assays; cell death measurements in RPE cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional KD phenotype, single lab","pmids":["33783309"],"is_preprint":false},{"year":2022,"finding":"KRT8 knockdown in lung adenocarcinoma cells suppressed cell proliferation, migration, invasion, and EMT, and significantly inhibited NF-κB signaling, suggesting KRT8 promotes lung carcinogenesis at least in part through NF-κB pathway activation.","method":"siRNA knockdown of KRT8 in LUAD cell lines; proliferation, migration, and invasion assays; apoptosis assays; Western blotting for EMT markers and NF-κB pathway components","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single knockdown approach, pathway placement based on Western blot only","pmids":["35664775"],"is_preprint":false},{"year":2023,"finding":"Phosphorylation of KRT8 at Ser43 by overloading-activated RHOA-PKN (protein kinase N) impedes Golgi-resident RAB33B trafficking, suppressing autophagosome initiation and contributing to intervertebral disc degeneration (IDD). Conditional knockout of Krt8 in nucleus pulposus cells aggravated load-induced IDD in vivo, while Krt8 overexpression conferred protection against overloading-induced apoptosis. Knockdown of Pkn1/Pkn2 at early IDD stages ameliorated disc degeneration.","method":"Discovery-driven phosphoproteomics; conditional Krt8 knockout mouse; Krt8 overexpression in NP cells; in vitro compressive loading; in vivo lumbar instability and tail compression models; MRI and histology; AAV-mediated gene delivery","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — specific phosphorylation site identified, in vivo genetic model, multiple orthogonal in vitro and in vivo validations","pmids":["36897022"],"is_preprint":false},{"year":2024,"finding":"NAT10 promotes prostate cancer growth and metastasis by acetylating KRT8 mRNA (N4-acetylcytidine, ac4C modification), which increases KRT8 mRNA stability, elevates KRT8 protein levels, and thereby promotes epithelial-mesenchymal transition (EMT) and cell migration.","method":"NAT10 knockdown and overexpression; RNA immunoprecipitation (RIP) for ac4C-modified KRT8 mRNA; mRNA stability assays; EMT and migration assays in prostate cancer cell lines","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — RIP validation of mRNA acetylation with functional downstream assays, single lab","pmids":["38922788"],"is_preprint":false},{"year":2024,"finding":"TEAD4 transcriptionally regulates Krt8 expression in mouse preimplantation embryos. TEAD4 knockout by base editing reduces Krt8 expression and causes developmental arrest at the morula stage with dramatic decrease in nuclear YAP in outside cells, placing Krt8 downstream of TEAD4 and upstream of Hippo/YAP signaling in trophectoderm epithelium integrity. This regulatory axis is not conserved in bovine embryos.","method":"Base editing-mediated Tead4 knockout in mouse embryos; RNA-seq of knockout embryos; immunofluorescence for KRT8, CDX2, GATA3, and YAP; comparative analysis in bovine embryos","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with RNA-seq and protein-level validation, species comparison, single lab","pmids":["38206180"],"is_preprint":false},{"year":2011,"finding":"KRT8 haplotype variants are associated with cystic fibrosis disease severity and CFTR-mediated residual chloride secretion in F508del-CFTR homozygotes. One KRT8 haplotype is associated with residual chloride secretion and milder disease, suggesting that KRT8/K18 heterodimeric intermediate filaments are an essential component for proper CFTR apical membrane targeting in epithelial cells.","method":"Candidate gene association study with microsatellite and SNP markers in CF patient sibpairs stratified by disease severity and intestinal chloride secretion phenotypes","journal":"BMC medical genetics","confidence":"Low","confidence_rationale":"Tier 4 — genetic association only, no direct mechanistic experiment, but provides in vivo human evidence for KRT8 role in CFTR trafficking","pmids":["21548936"],"is_preprint":false},{"year":2017,"finding":"CRF (corticotropin-releasing factor) increases intestinal epithelial permeability by upregulating CK8 expression. CK8 upregulation activates RhoA signaling, promotes actin remodeling, and decreases expression of the tight junction protein ZO-1. CK8 silencing blocked CRF-induced RhoA activation and ZO-1 downregulation but not claudin-1/occludin changes, placing CK8 as a partial mediator between CRF receptor signaling and tight junction regulation.","method":"CRF treatment of HT29 intestinal epithelial cells; CK8-silenced cells via shRNA; FITC-dextran permeability assay; transmission electron microscopy of tight junctions; immunoprecipitation for RhoA activity; immunoblotting and immunofluorescence","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — shRNA knockdown with multiple functional readouts and defined pathway placement, single lab","pmids":["29179184"],"is_preprint":false},{"year":2020,"finding":"CREB1 transcriptionally suppresses microRNA-186, which in turn targets KRT8 mRNA for degradation. By suppressing miR-186, CREB1 stabilizes KRT8 expression. Elevated KRT8 then increases HIF-1α expression, and HIF-1α blocks the tumor-suppressive effects of CREB1 silencing on gastric cancer cell growth, invasion, and EMT.","method":"CREB1 knockdown in gastric cancer cell lines; luciferase reporter assays for miR-186 promoter; miR-186 overexpression; KRT8 overexpression rescue experiments; HIF-1α pathway analysis; proliferation, invasion, and EMT assays","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established through multiple rescue experiments, luciferase validation, single lab","pmids":["33061604"],"is_preprint":false}],"current_model":"KRT8 is a type II simple epithelial keratin that obligatorily heterodimerizes with type I partner K18 to form tetrameric assembly units and then intermediate filaments; it is required for apical membrane domain organization and microtubule anchoring in simple epithelia, is phosphorylated by PKC (at multiple sites including Ser43 by RHOA-PKN under mechanical overload) to regulate filament dynamics and autophagosome initiation, physically interacts with plectin to tether mitochondria and facilitate mitophagy, is ectopically induced in cardiomyocytes by TNF-α/NF-κB to confer cardioprotection at intercalated discs, marks a transitional stem cell state during alveolar regeneration that persists aberrantly in lung fibrosis, and modulates EMT/migration through multiple signaling axes including integrin-FAK-TGF-β/SMAD, NF-κB, RhoA-actin/tight junction, and CREB1-miR-186-HIF-1α, with its mRNA stability regulated by NAT10-mediated ac4C acetylation."},"narrative":{"teleology":[{"year":1982,"claim":"Establishing KRT8 as a distinct type II simple epithelial keratin that forms obligate heteropolymeric filaments with type I partners answered the foundational question of intermediate filament subunit identity and pairing rules in simple epithelia.","evidence":"Two-dimensional gel electrophoresis and immunological characterization across normal epithelia, tumors, and cultured cells","pmids":["6186379"],"confidence":"High","gaps":["Stoichiometry and assembly pathway of heteropolymers not yet defined","In vivo requirement for K8/K18 filaments not tested genetically"]},{"year":1992,"claim":"Demonstrating that PKC selectively phosphorylates K8 over K18 in hepatocytes established that K8 is a regulated signaling target rather than a passive structural scaffold, linking kinase signaling to filament reorganization.","evidence":"Metabolic radiolabeling of TPA-treated primary mouse hepatocytes with immunoprecipitation; PKC down-regulation controls","pmids":["1283312"],"confidence":"Medium","gaps":["Specific phosphorylation sites on K8 not mapped","Functional consequence of phosphorylation on filament mechanics not quantified"]},{"year":2001,"claim":"KRT8-knockout mice revealed that K8-based filaments are required for apical membrane protein retention, syntaxin 3 localization, and microtubule anchoring in intestinal enterocytes, establishing K8 as essential for epithelial polarity beyond mechanical support.","evidence":"Analysis of CK8-null mouse intestinal epithelia by immunofluorescence for apical markers, syntaxin 3, γ-tubulin, and microtubules","pmids":["11171325"],"confidence":"High","gaps":["Molecular mechanism linking K8 filaments to syntaxin 3 and γ-tubulin anchoring unknown","Whether CFTR mistargeting in KRT8 absence directly drives disease phenotypes not tested"]},{"year":2011,"claim":"Biophysical reconstitution of K8/K18 assembly defined the tetramer as the obligate starter unit, measured filament persistence length, and showed Mg²⁺-dependent stiffening, providing the quantitative framework for understanding K8/K18 filament mechanics.","evidence":"Analytical ultracentrifugation, electron microscopy, and persistence length measurements on recombinant K8, K18, and K8/K18 mixtures","pmids":["22085677"],"confidence":"High","gaps":["How post-translational modifications alter assembly kinetics and persistence length not addressed","Lateral association mechanism not resolved at atomic level"]},{"year":2015,"claim":"HDX-MS mapping of K8/K18 complexes across assembly states provided the first direct structural evidence that IF-consensus motifs at rod-domain termini drive filament elongation via head-to-tail contacts, resolving a long-standing structural question.","evidence":"Hydrogen-deuterium exchange mass spectrometry of recombinant K8/K18 at monomer, tetramer, and filament stages","pmids":["26434626"],"confidence":"High","gaps":["No high-resolution atomic structure of the assembled filament","Role of individual head-to-tail contact residues not tested by mutagenesis"]},{"year":2015,"claim":"Discovery that TNF-α/NF-κB induces ectopic K8/K18 in desmin-null cardiomyocytes, where the filaments localize to intercalated discs and preserve mitochondrial function, revealed an unexpected cardioprotective role for K8 outside its canonical epithelial context.","evidence":"Desmin-null and aortic constriction mouse models; immunofluorescence and EM of intercalated discs; mitochondrial assays; NF-κB conditional approaches; human failing myocardium","pmids":["26280121"],"confidence":"High","gaps":["Whether K8/K18 expression is a general cardiomyocyte stress response or specific to desmin loss unknown","Molecular mechanism of K8/K18 at intercalated discs not defined"]},{"year":2016,"claim":"In vitro reconstitution showed plectin crosslinks K8/K18 networks at intersection points without bundling and significantly increases network rigidity, validated by AFM of plectin-depleted epithelial cells, establishing plectin as a major modulator of K8/K18 cytoskeletal mechanics.","evidence":"Reconstituted K8/K18 networks with purified plectin; microrheology; AFM of detergent-extracted A431 cells with plectin siRNA","pmids":["27489177"],"confidence":"High","gaps":["How plectin–K8 interaction is regulated by phosphorylation in cells not tested in this system","Other crosslinkers that may cooperate with plectin not identified"]},{"year":2017,"claim":"Studies in RPE cells and gastric cancer cells converged on the principle that KRT8 phosphorylation state governs a switch between cytoprotective autophagy and pathological EMT, with ERK1/2-mediated phosphorylation promoting EMT through integrin β1–FAK–SMAD2/3 and related signaling axes.","evidence":"Pharmacological autophagy and MAPK modulation in RPE cells; KRT8 overexpression/knockdown with EMT and pathway readouts in gastric cancer cells","pmids":["28045574","27865045"],"confidence":"Medium","gaps":["Precise phosphorylation sites driving the autophagy-EMT switch not mapped at this stage","Whether the same switch operates in normal epithelia unknown"]},{"year":2020,"claim":"Single-cell transcriptomics and lineage tracing identified a Krt8+ transitional stem cell state as a convergent intermediate during alveolar regeneration that persists aberrantly in human lung fibrosis, positioning KRT8 as a marker and potential functional participant in failed regeneration.","evidence":"Time-series scRNA-seq of bleomycin-injured mouse lungs; lineage tracing; trajectory modeling; validation in multiple injury models and human fibrosis tissue","pmids":["32678092"],"confidence":"High","gaps":["Whether KRT8 is functionally required for the transitional state or merely a marker not determined","Signals that resolve versus perpetuate the Krt8+ state not identified"]},{"year":2020,"claim":"Phospho-site mutagenesis showed that phosphorylated KRT8 is required for autophagosome–lysosome fusion during TGF-β2-induced EMT, placing KRT8 phosphorylation as a direct regulator of autophagic flux rather than just filament dynamics.","evidence":"KRT8 phospho-site mutagenesis and siRNA knockdown in RPE cells; autophagy flux and EMT assays","pmids":["32022439"],"confidence":"Medium","gaps":["Identity of the specific phosphorylation site(s) involved in fusion step not fully resolved","Mechanism by which phospho-KRT8 facilitates membrane fusion unknown"]},{"year":2021,"claim":"KRT8 physically interacts with plectin to tether mitochondria, and oxidative stress–induced KRT8 phosphorylation disrupts this interaction, impairing mitophagy and causing necrotic cell death—directly linking KRT8 phosphorylation to mitochondrial quality control.","evidence":"Reciprocal co-immunoprecipitation of KRT8–plectin; siRNA knockdown; mitochondrial morphology, membrane potential, and mitophagy flux assays in RPE cells","pmids":["33783309"],"confidence":"Medium","gaps":["Phosphorylation site(s) governing plectin dissociation not mapped","Whether this mechanism operates in epithelia beyond RPE not tested"]},{"year":2023,"claim":"Identification of Ser43 as the RHOA–PKN phosphorylation site on KRT8 that impedes RAB33B-dependent autophagosome initiation provided the first site-specific mechanistic link between mechanical overloading, KRT8 phosphorylation, and autophagy suppression in intervertebral disc degeneration.","evidence":"Phosphoproteomics; conditional Krt8 knockout and overexpression in nucleus pulposus; in vivo lumbar instability and tail compression models; AAV-mediated gene delivery","pmids":["36897022"],"confidence":"High","gaps":["Whether Ser43 phosphorylation also governs the plectin–KRT8 interaction is untested","Structural basis for how pSer43-KRT8 sequesters RAB33B not resolved"]},{"year":2024,"claim":"NAT10-mediated ac4C modification of KRT8 mRNA was shown to stabilize KRT8 transcript and elevate protein levels driving EMT in prostate cancer, revealing an epitranscriptomic layer of KRT8 regulation beyond transcription and phosphorylation.","evidence":"NAT10 knockdown/overexpression; RNA immunoprecipitation for ac4C-modified KRT8 mRNA; mRNA stability and EMT assays in prostate cancer cells","pmids":["38922788"],"confidence":"Medium","gaps":["Specific ac4C sites on KRT8 mRNA not mapped","Whether ac4C modification of KRT8 mRNA occurs in normal epithelia unknown"]},{"year":2024,"claim":"TEAD4 was identified as a direct transcriptional regulator of Krt8 in mouse preimplantation embryos, positioning KRT8 downstream of Hippo signaling in trophectoderm specification, though this regulatory relationship is not conserved in bovine embryos.","evidence":"Base editing-mediated Tead4 knockout in mouse embryos; RNA-seq; immunofluorescence for KRT8, CDX2, GATA3, YAP; bovine comparison","pmids":["38206180"],"confidence":"Medium","gaps":["Whether TEAD4 directly binds the KRT8 promoter (ChIP) not shown","Species-specific regulatory logic not explained mechanistically"]},{"year":null,"claim":"Major unresolved questions include: (1) the atomic-resolution structure of the assembled K8/K18 filament, (2) whether KRT8 is functionally required for—or merely marks—the transitional alveolar stem cell state in lung regeneration, and (3) the structural basis by which Ser43 phosphorylation on KRT8 interferes with RAB33B trafficking to suppress autophagosome initiation.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of assembled K8/K18 filament","Functional requirement of KRT8 in Krt8+ transitional state not tested by conditional deletion in that lineage","Structural mechanism of pSer43-KRT8 interaction with RAB33B unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,8,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,4,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,16,18]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,22,23]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,20]}],"complexes":["K8/K18 intermediate filament"],"partners":["KRT18","KRT19","PLEC","PKN1","RAB33B","NAT10","TEAD4"],"other_free_text":[]},"mechanistic_narrative":"KRT8 is a type II simple epithelial keratin that obligatorily heterodimerizes with its type I partner K18 to form tetrameric assembly units that polymerize into intermediate filaments, providing mechanical integrity and organizing the apical membrane domain and microtubule anchoring in simple epithelia [PMID:6186379, PMID:22085677, PMID:11171325]. Plectin crosslinks the K8/K18 network at filament intersection points to modulate cytoskeletal stiffness and tether mitochondria for mitophagy, while site-specific phosphorylation—by PKC under mechanical load and by RHOA–PKN at Ser43 under overloading—regulates filament dynamics, autophagosome initiation via RAB33B trafficking, and autophagosome–lysosome fusion [PMID:27489177, PMID:33783309, PMID:36897022, PMID:32022439]. KRT8 marks a transitional stem cell state during alveolar regeneration that persists aberrantly in human lung fibrosis, and ectopic TNF-α/NF-κB–driven K8/K18 expression in cardiomyocytes localizes to intercalated discs and confers cardioprotection in the absence of desmin [PMID:32678092, PMID:26280121]. In multiple carcinoma contexts, KRT8 promotes epithelial–mesenchymal transition through integrin β1–FAK–TGF-β/SMAD, NF-κB, and RhoA–tight junction signaling axes, and its mRNA stability is regulated by NAT10-mediated ac4C acetylation [PMID:27865045, PMID:29179184, PMID:38922788]."},"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 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K8/K18 filaments assemble several times faster than vimentin and desmin, with a persistence length of ~300 nm that increases to ~480 nm in the presence of MgCl2.\",\n      \"method\": \"Recombinant protein reconstitution, analytical ultracentrifugation (sedimentation velocity and equilibrium), in vitro filament assembly kinetics with electron microscopy\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with multiple orthogonal biophysical methods\",\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, which mediate head-to-tail dimer-dimer interactions, become distinctly more protected upon filament formation, while flexible linker regions remain dynamic. Homomeric K8 forms dimers/tetramers whereas monomeric K18 is stabilized only upon K8 co-assembly.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry of purified recombinant K8/K18 at dimer, tetramer, and filament assembly states\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — novel structural dynamics method with multiple assembly-state comparisons\",\n      \"pmids\": [\"26434626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CK8 is phosphorylated in hepatocytes in a protein kinase C-dependent manner: TPA (a PKC activator) induces transient CK8 phosphorylation within 15 min, and this effect is abolished after PKC down-regulation by prolonged TPA treatment, identifying CK8 as an in vivo substrate for PKC.\",\n      \"method\": \"32P metabolic labeling of primary mouse hepatocytes, TPA stimulation, PKC down-regulation, indirect immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean pharmacological manipulation with phosphorylation readout, single lab\",\n      \"pmids\": [\"1283312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Compressive mechanical load activates protein kinase C, which phosphorylates CK8 in nucleus pulposus cells, leading to CK8 disassembly and downregulation in a time- and magnitude-dependent manner, linking mechanical stress to CK8 degradation in intervertebral disc degeneration.\",\n      \"method\": \"In vitro compressive load model of NP cells, Western blot for phospho-CK8, PKC inhibitor experiments\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement with pharmacological inhibition, single lab\",\n      \"pmids\": [\"24166186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Under overloading, RHOA activates PKN1/2 (protein kinase N), which phosphorylates KRT8 at Ser43, impairing RAB33B-dependent trafficking from the Golgi and suppressing autophagosome initiation, thereby contributing to intervertebral disc degeneration. Conditional knockout of Krt8 in nucleus pulposus aggravates load-induced IDD, and overexpression is protective.\",\n      \"method\": \"In vivo conditional knockout mouse model, AAV-mediated overexpression, phosphoproteomics, co-IP, RAB33B trafficking assay, autophagy flux assays, site-directed mutagenesis (Ser43)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vivo KO, mutagenesis, and mechanistic pathway dissection\",\n      \"pmids\": [\"36897022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KRT8 phosphorylation (via MAPK1/ERK2 and MAPK3/ERK1) under oxidative stress promotes pathological EMT of retinal pigment epithelium cells, while autophagy-driven upregulation of total KRT8 is cytoprotective. The two processes are thus mechanistically separable: unphosphorylated KRT8 is protective, whereas phospho-KRT8 drives EMT.\",\n      \"method\": \"siRNA knockdown of KRT8 in RPE cells, autophagy inhibitors, MAPK inhibitors, Western blot, immunofluorescence, EMT marker analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype plus pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"28045574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Phosphorylated KRT8 (p-KRT8) facilitates autophagosome-lysosome fusion during TGF-β2-induced EMT of RPE cells; knockdown or mutagenesis of the critical KRT8 phosphorylation site impairs autophagic flux by blocking autophagosome-lysosome fusion.\",\n      \"method\": \"siRNA knockdown, site-directed mutagenesis of KRT8 phosphorylation site, autophagy flux assay, immunofluorescence co-localization in RPE cells and PVR patient membranes\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus KD with defined mechanistic readout, single lab\",\n      \"pmids\": [\"32022439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KRT8 physically interacts with PLEC (plectin) at the mitochondrial outer membrane and facilitates mitochondrial fission-mediated mitophagy. KRT8 phosphorylation under oxidative stress reduces the KRT8-PLEC-mitochondria association, impairing mitophagy and leading to necrotic cell death in RPE cells.\",\n      \"method\": \"Co-IP of KRT8 with PLEC and TOMM20 (mitochondrial marker), KRT8 KD, mitophagy flux assay, mitochondrial morphology imaging, oxidative stress model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal co-IP with functional KD phenotype, single lab\",\n      \"pmids\": [\"33783309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TNF-α induces NF-κB-mediated ectopic expression of K8 and K18 in cardiomyocytes (normally epithelial-specific), where K8/K18 form an alternative intermediate filament network that localizes to intercalated discs, maintains intercalated disc structure and mitochondrial integrity, and confers cardioprotection in desmin-deficient mice.\",\n      \"method\": \"Genetic heart failure mouse model (desmin KO), transverse aortic constriction, immunofluorescence, electron microscopy, NF-κB inhibition, mitochondrial function assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic mouse models with mechanistic pathway placement and structural readouts\",\n      \"pmids\": [\"26280121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss of CK8 in mouse enterocytes (the only epithelial cell type in CK8-null mice that lacks any compensating keratin partner) leads to loss of syntaxin 3 and apical membrane proteins (alkaline phosphatase, sucrase isomaltase, CFTR) as cells progress along the villus, and mislocalization of γ-tubulin with disorganized microtubules, establishing a role for K8-containing IFs in organizing the apical domain of polarized simple epithelia.\",\n      \"method\": \"CK8 knockout mouse model, immunofluorescence with anti-CK and apical marker antibodies, morphological analysis of villus enterocytes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO with specific molecular and cellular phenotypes at apical membrane\",\n      \"pmids\": [\"11171325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of desmosomal plaque protein PKP3 increases PRL3 phosphatase levels, which dephosphorylates K8, stabilizing K8 filaments; this increased K8 promotes cell migration, lamellipodia formation, soft-agar colony formation, and metastasis. K8 knockdown in PKP3-KD cells reverses these phenotypes, placing K8 downstream of PKP3/PRL3 in a pathway controlling transformation and metastasis.\",\n      \"method\": \"shRNA knockdown of PKP3 and K8, PRL3 western blot, phospho-K8 analysis, migration/invasion assays, soft agar assay, nude mouse xenograft\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by double knockdown with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"22701666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In BSp73 pancreatic adenocarcinoma cells (vimentin+, keratin−), transfection of K8 alone stabilizes endogenous K19, forming K8/K19 filaments and increasing motility and tumorigenicity, whereas K18 expression suppresses motility and tumorigenicity in a dose-dependent manner, demonstrating functionally distinct roles for K8 versus K18 in the same cellular context.\",\n      \"method\": \"Stable transfection of K8 and K18 individually or in combination into keratin-null tumor cells, soft agar assay, motility assay, syngeneic tumor injection\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain-of-function with multiple phenotypic readouts; K8 specifically stabilizes K19, single lab\",\n      \"pmids\": [\"9152022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KRT8 genetic variants (haplotypes spanning the KRT8 gene) are associated with CF disease severity and with CFTR-mediated residual chloride secretion in F508del-CFTR homozygous patients, suggesting that K8/K18 heterodimeric IF networks are required for proper targeting of CFTR to the apical membrane in epithelial cells.\",\n      \"method\": \"Genetic association study using microsatellite and SNP markers in contrasting CF patient subpopulations (mild vs. severe), haplotype analysis\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association only, no direct functional experiment on KRT8 mechanism\",\n      \"pmids\": [\"21548936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"K8/K18 IF networks are mechanically regulated by monovalent cations (potassium causes bundling and stiffening) and by the cytolinker protein plectin, which crosslinks filaments at intersection points without bundling them; both mechanisms increase network rigidity, and plectin knockdown in A431 epithelial cells decreases cytoskeletal stiffness.\",\n      \"method\": \"In vitro reconstituted K8/K18 networks with microrheology, potassium titration, recombinant plectin addition; atomic force microscopy of detergent-extracted cells with plectin siRNA knockdown\",\n      \"journal\": \"Soft matter\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro networks with microrheology plus cellular validation, multiple methods\",\n      \"pmids\": [\"27489177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KRT8 overexpression in gastric cancer cells enhances proliferation and migration, activates integrin β1-FAK signaling leading to EMT, and increases p-Smad2/3 levels, placing KRT8 upstream of TGFβ-dependent signaling events that drive EMT.\",\n      \"method\": \"KRT8 overexpression and siRNA knockdown in gastric cancer cells, migration assay, western blot for integrin β1, FAK, p-Smad2/3, EMT markers\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — overexpression/KD with pathway markers but no direct binding or reconstitution, single lab\",\n      \"pmids\": [\"27865045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 acetylates KRT8 mRNA at N4-cytidine (ac4C), increasing KRT8 mRNA stability and protein levels, which in turn promotes EMT and cell migration in prostate cancer cells.\",\n      \"method\": \"acRIP-seq (ac4C RNA immunoprecipitation sequencing), NAT10 overexpression/knockdown, KRT8 mRNA stability assay, cell migration assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA modification identified by acRIP-seq with functional consequence, single lab\",\n      \"pmids\": [\"38922788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRF increases intestinal epithelial permeability by upregulating CK8 expression, activating the RhoA signaling pathway, promoting actin remodeling, and decreasing tight junction protein ZO-1 expression; CK8 silencing blocks CRF-induced RhoA activation and ZO-1 decrease but not claudin-1/occludin downregulation.\",\n      \"method\": \"shRNA knockdown of CK8 in HT29 cells, CRF stimulation, FITC-dextran permeability assay, immunoprecipitation for RhoA activity, western blot and immunofluorescence for tight junction proteins\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined pathway placement via RhoA activity assay and permeability readout, single lab\",\n      \"pmids\": [\"29179184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD4 directly regulates Krt8 expression in mouse preimplantation embryos: Tead4 knockout reduces Krt8 levels in morula-stage embryos and causes developmental arrest; nuclear YAP is also dramatically decreased in outside cells of Tead4-deficient morula, establishing a TEAD4→KRT8/YAP regulatory axis in trophectoderm epithelium integrity.\",\n      \"method\": \"Base-editing Tead4 knockout in mouse embryos, RNA-seq, immunofluorescence for Krt8 and nuclear YAP\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic KO with transcriptomic and protein-level validation, single lab\",\n      \"pmids\": [\"38206180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KRT8 plays a required role in germ cell migration during ovarian follicle formation: KRT8 is highly expressed in DDX4ec primordial germ cell-like cells derived from human pluripotent stem cells, and KRT8 knockdown impairs germ cell migration.\",\n      \"method\": \"hPSC differentiation, flow cytometry for DDX4 surface expression, KRT8 siRNA knockdown, migration assay, xenograft co-culture model with human granulosa cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single KD with migration phenotype, no deeper pathway mechanism, single lab\",\n      \"pmids\": [\"33490911\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT8 (keratin 8) is a type II intermediate filament protein that obligately heterodimerizes with K18 to assemble into cytoskeletal filaments in simple epithelia; these filaments organize the apical membrane domain, regulate CFTR trafficking, modulate cell stiffness through plectin crosslinking, protect mitochondrial integrity via plectin-mediated mitophagy, and are regulated post-translationally by PKC- and PKN-mediated phosphorylation (at Ser43 by PKN downstream of RHOA under mechanical load) that controls filament disassembly, autophagosome initiation, and EMT, while NF-κB-driven ectopic expression of K8/K18 in cardiomyocytes forms a protective intercalated-disc network, and mRNA-level regulation occurs through NAT10-catalyzed ac4C modification that stabilizes KRT8 mRNA.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\n- Papers about KSHV/HHV-8 K8 or K8.1 (viral genes, not human KRT8): EXCLUDE (alias collision — viral ORF K8/K8.1)\n- Papers about rotavirus K8 strain: EXCLUDE (alias collision)\n- Papers about RC-K8 cell line (B-lymphoma, REL oncogene): EXCLUDE (alias collision)\n- Papers about Lactobacillus plantarum K8: EXCLUDE (microbial)\n- Papers about Pseudomonas phage K8: EXCLUDE (microbial)\n- Papers about Vibrio parahaemolyticus O4:K8: EXCLUDE (microbial)\n- Papers about Acinetobacter K8 capsular polysaccharide: EXCLUDE (microbial)\n- Papers about Streptococcus mutacin K8: EXCLUDE (microbial)\n- Papers about Kluyveromyces K8 mtDNA: EXCLUDE (unrelated)\n- Papers about CDK8 degrader LL-K8-22: EXCLUDE (CDK8, not KRT8)\n- Papers about histone H4 K8/K12 biotinylation: EXCLUDE (histone residue positions, not KRT8)\n- Papers about OsHDA706 H4K5/K8 deacetylation in rice: EXCLUDE (plant/histone)\n- Papers about E. coli K8 antigen: EXCLUDE (microbial)\n- Papers about RIG-I CARD2-Hel2i: EXCLUDE (unrelated)\n- Papers about Pseudomonas R plasmid BB-K8 amikacin resistance: EXCLUDE (microbial)\n- Papers about KRT8 (human keratin 8, canonical): KEEP\n\n**KEPT papers** (canonical human/mammalian KRT8):\n[1], [7], [8], [15], [17], [27] (complex formation K8/K18), [29] (thymic K5+K8+ progenitors), [32], [33], [35], [37], [38], [41], [46], [53], [55], [56], [62], [66], [69], [78], [80] (biomarker - exclude mechanistic), [90], [91], [92], [93], [97], [98], [99], plus curated papers [1](Moll 1982), [18](nomenclature).\n\nAlso KEEP: paper [27 in main list = \"Complex formation and kinetics...\"], [92], [98].\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1982,\n      \"finding\": \"KRT8 (cytokeratin 8, a type II keratin) was catalogued as a component of simple epithelial intermediate filaments; it is expressed predominantly in simple and some stratified epithelia and forms obligate heteropolymeric filaments with type I keratin partners.\",\n      \"method\": \"Two-dimensional gel electrophoresis and immunological characterization of keratin proteins from normal epithelia, tumors, and cultured cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational biochemical characterization, >5000 citations, multiple tissue types\",\n      \"pmids\": [\"6186379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CK8 is preferentially phosphorylated over CK18 in primary hepatocytes; treatment with the protein kinase C activator TPA (phorbol ester) induces a transient, sustained increase in CK8 phosphorylation but not CK18 phosphorylation, identifying CK8 as an in vivo substrate of PKC. This phosphorylation was accompanied by cytokeratin aggregate formation in some cells but not wholesale filament disruption.\",\n      \"method\": \"Metabolic radiolabeling of primary mouse hepatocyte cultures treated with TPA, followed by immunoprecipitation and indirect immunofluorescence microscopy; PKC down-regulation experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — PKC activation/downregulation with biochemical readout, single lab\",\n      \"pmids\": [\"1283312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In a pancreatic adenocarcinoma model (BSp73), expression of K8 alone stabilized endogenous K19 and enabled keratin filament formation (K8/K19 network), whereas K18 expression was unstable without K8 co-expression. K8/K19-expressing clones retained motility and tumorigenicity, while K18-expressing clones showed dramatically suppressed tumorigenicity and reduced soft-agar growth, indicating that K8 and K18 have opposing roles in regulating cell motility and tumor progression.\",\n      \"method\": \"Stable transfection of K8 and K18 individually and in combination into keratin-null adenocarcinoma cells; soft-agar colony assays, motility assays, syngeneic tumor injection\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain-of-function with multiple functional readouts, single lab\",\n      \"pmids\": [\"9152022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In CK8-null mouse intestinal villus enterocytes (the only cell type lacking IF partners and thus without keratin filaments), apical membrane proteins (alkaline phosphatase, sucrase-isomaltase, CFTR) were progressively lost along the villus, syntaxin 3 was absent, and γ-tubulin mislocalized from its normal sub-apical position with disorganized microtubules. This establishes that the KRT8-based intermediate filament network is required for maintaining the apical membrane domain organization and microtubule anchoring in simple polarized epithelia.\",\n      \"method\": \"Analysis of CK8-knockout mice; immunofluorescence localization of apical markers, syntaxin 3, γ-tubulin, and microtubules in intestinal epithelia and hepatocytes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple orthogonal phenotypic readouts, mechanistic pathway placement\",\n      \"pmids\": [\"11171325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Recombinant human K8 and K18 assemble into intermediate filaments through a defined pathway: K8 alone forms dimers to tetramers, K18 alone is monomeric, but equimolar K8/K18 mixtures renature as homogeneous tetrameric complexes. These tetramers are the starter units for filament assembly, which proceeds several times faster than vimentin or desmin. The persistence length of K8/K18 filaments is ~300 nm, increasing to ~480 nm with Mg²⁺, indicating Mg²⁺ stiffens the filament by affecting subunit interactions.\",\n      \"method\": \"Analytical ultracentrifugation (sedimentation velocity and equilibrium), electron microscopy of filaments assembled at various protein concentrations and time points, persistence length measurements\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal biophysical methods\",\n      \"pmids\": [\"22085677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of the desmosomal plaque protein plakophilin3 (PKP3) in HCT116 cells elevates PRL3 (phosphatase of regenerating liver 3) protein levels, which reduces phosphorylation of K8. The resulting stabilized, dephosphorylated K8 promotes increased cell migration, lamellipodia formation, soft-agar colony formation, and metastasis in nude mice. K8/PKP3 double knockdown reversed these phenotypes, placing K8 downstream of PRL3 in a dephosphorylation-dependent mechanism of tumor progression.\",\n      \"method\": \"shRNA knockdown of PKP3 and K8 individually and in combination; Western blotting for PRL3 and phospho-K8; wound-healing and lamellipodia assays; soft-agar colony formation; nude mouse tumorigenesis and metastasis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, genetic epistasis, single lab\",\n      \"pmids\": [\"22701666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CK8 expression is down-regulated in human intervertebral disc degeneration (IDD) nucleus pulposus (NP) cells. Compressive mechanical loads applied to cultured NP cells cause CK8 phosphorylation and filament disassembly in a time- and magnitude-dependent manner. Protein kinase C (PKC) activation is a critical molecular mediator of compressive load-induced CK8 phosphorylation and downregulation.\",\n      \"method\": \"Western blotting and qRT-PCR of human NP tissue samples; in vitro NP cell compressive loading with pharmacological PKC pathway analysis\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human tissue validation combined with mechanistic in vitro loading experiments, single lab\",\n      \"pmids\": [\"24166186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TNF-α, acting via NF-κB, drives ectopic expression of keratin 8 (K8) and keratin 18 (K18) in cardiomyocytes of desmin-deficient mice. The ectopic K8/K18 network localizes predominantly to intercalated discs, maintains normal intercalated disc structure and mitochondrial integrity and function, and confers cardioprotection. Loss of the K8/K18 network in this context leads to a maladaptive cardiac phenotype after aortic constriction.\",\n      \"method\": \"Genetic heart failure mouse models (desmin-null and transverse aortic constriction); immunofluorescence and electron microscopy of intercalated discs; mitochondrial function assays; NF-κB reporter and conditional knockout approaches; human failing myocardium immunostaining\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models, orthogonal mechanistic readouts, replicated in human tissue, published in high-impact journal\",\n      \"pmids\": [\"26280121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) of K8/K18 complexes mapped regions of differential structural dynamics at the tetramer versus filament stages. The IF-consensus motifs at the ends of the central α-helical rod domain, which mediate head-to-tail dimer-dimer interactions, become significantly more protected (less exchangeable) upon filament formation, providing direct structural evidence that these regions drive filament elongation. Homomeric K8 and K18 preparations showed distinct exchange patterns from the heterodimer, revealing partner-dependent stabilization.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) of recombinant K8, K18, and K8/K18 complexes at multiple assembly states (monomer/dimer, tetramer, filament)\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural method (HDX-MS) applied across multiple assembly states with functional interpretation\",\n      \"pmids\": [\"26434626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Plectin crosslinks K8/K18 intermediate filament networks at filament intersection points without inducing bundle formation, and plectin-mediated crosslinking increases network rigidity when added at amounts above ~20% of the plectin present in cells. In contrast, potassium ions cause K8/K18 filament bundling that also significantly stiffens the network. In detergent-extracted epithelial cells, downregulation of plectin to ~10% of normal levels significantly decreased cytoskeletal stiffness, establishing plectin as a major modulator of K8/K18 network mechanics.\",\n      \"method\": \"In vitro reconstitution of K8/K18 networks with potassium ions or purified plectin; microrheology; atomic force microscopy of detergent-extracted A431 cells with plectin siRNA knockdown\",\n      \"journal\": \"Soft matter\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with orthogonal in situ validation, multiple biophysical methods\",\n      \"pmids\": [\"27489177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KRT8 upregulation following autophagy induction provides a cytoprotective role in retinal pigment epithelium (RPE) cells under oxidative stress. However, phosphorylation of KRT8 (mediated by MAPK1/ERK2 and MAPK3/ERK1) promotes pathological epithelial-mesenchymal transition (EMT) of RPE cells. Inhibition of autophagy further promotes EMT, which can be reversed by MAPK inhibition, establishing a dual role for KRT8 in RPE pathophysiology dependent on its phosphorylation state.\",\n      \"method\": \"RPE cell culture with oxidative stress; pharmacological autophagy inhibition and activation; MAPK1/3 inhibitors; immunofluorescence and Western blotting for phospho-KRT8, EMT markers, and autophagy markers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological interventions with defined pathway placement, single lab\",\n      \"pmids\": [\"28045574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KRT8 overexpression in gastric cancer cells enhanced proliferation and migration, and was associated with integrin β1-FAK-induced epithelial-mesenchymal transition (EMT) in high-KRT8 cells. KRT8 overexpression increased p-SMAD2/3 levels, linking KRT8 to TGF-β-dependent signaling and EMT.\",\n      \"method\": \"KRT8 siRNA knockdown and overexpression in gastric cancer cell lines; proliferation and migration assays; Western blotting for EMT markers, integrin β1-FAK pathway components, and p-SMAD2/3\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional cell biology with partial pathway placement, single lab\",\n      \"pmids\": [\"27865045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A unique Krt8+ transitional stem cell state arises during alveolar regeneration from both airway and alveolar stem cell lineages converging after lung injury. These Krt8+ cells display squamous morphology, activation of p53 and NF-κB transcriptional programs, and features of cellular senescence. In human lung fibrosis, this Krt8+ transitional state aberrantly persists, establishing a distinct cell-cell communication network with mesenchyme and macrophages.\",\n      \"method\": \"Time-series single-cell RNA-seq of bleomycin-injured mouse lungs; lineage tracing; trajectory modeling; validation in multiple independent lung injury models and human fibrosis samples\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lineage tracing plus scRNA-seq trajectory analysis, replicated across multiple models and human tissue\",\n      \"pmids\": [\"32678092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KRT8 phosphorylation correlates with autophagy progression during TGF-β2-induced EMT in retinal pigment epithelial cells. Knockdown of KRT8 or mutagenesis of its critical phosphorylation site impairs autophagosome-lysosome fusion, demonstrating that phosphorylated KRT8 is required for completion of autophagic flux during EMT.\",\n      \"method\": \"siRNA knockdown and phospho-site mutagenesis of KRT8 in RPE cells; TGF-β2-induced EMT; Western blotting and immunofluorescence for autophagy markers and EMT markers; transwell migration assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of specific phosphorylation site with defined functional consequence, single lab\",\n      \"pmids\": [\"32022439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cisplatin upregulates KRT8 in cancer-associated fibroblasts (CAFs), and this KRT8 upregulation suppresses AKT signaling in CAFs, attenuating their ability to promote lung cancer cell migration and invasion. Stimulation of AKT activity (with SC79) reversed KRT8's inhibitory effect on migration, linking KRT8 to suppression of the AKT pathway in CAFs.\",\n      \"method\": \"KRT8 knockdown/overexpression in CAFs; co-culture with lung cancer cells; wound-healing and transwell invasion assays; Western blotting for AKT pathway; nude mouse tumor models\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic depth, CAF-specific context\",\n      \"pmids\": [\"32280245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Analysis of zebrafish periderm enhancers identified a regulatory SNP near the KRT8/KRT18 locus at 12q13 that lies within a periderm enhancer controlling KRT18/KRT8 expression. Reporter assays and deletion analyses confirmed this SNP functionally regulates KRT8/KRT18 expression in periderm cells and is associated with non-syndromic orofacial clefting risk.\",\n      \"method\": \"ATAC-seq on zebrafish periderm and human oral epithelium; gapped-kmer SVM classifiers; reporter assays; CRISPR deletion analysis in zebrafish\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ATAC-seq plus functional reporter and deletion validation, relevant to KRT8 transcriptional regulation\",\n      \"pmids\": [\"32031521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KRT8 physically interacts with the cytolinker protein PLEC (plectin) to tether mitochondria and facilitate mitochondrial fission-mediated mitophagy in RPE cells under oxidative stress. When KRT8 is phosphorylated under oxidative stress conditions, the KRT8-PLEC association is disrupted, impairing mitophagy and leading to accumulation of damaged mitochondria and necrotic cell death.\",\n      \"method\": \"Co-immunoprecipitation to identify KRT8-PLEC interaction; siRNA knockdown of KRT8 and PLEC; mitochondrial morphology and membrane potential assays; mitophagy flux assays; cell death measurements in RPE cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional KD phenotype, single lab\",\n      \"pmids\": [\"33783309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KRT8 knockdown in lung adenocarcinoma cells suppressed cell proliferation, migration, invasion, and EMT, and significantly inhibited NF-κB signaling, suggesting KRT8 promotes lung carcinogenesis at least in part through NF-κB pathway activation.\",\n      \"method\": \"siRNA knockdown of KRT8 in LUAD cell lines; proliferation, migration, and invasion assays; apoptosis assays; Western blotting for EMT markers and NF-κB pathway components\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single knockdown approach, pathway placement based on Western blot only\",\n      \"pmids\": [\"35664775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Phosphorylation of KRT8 at Ser43 by overloading-activated RHOA-PKN (protein kinase N) impedes Golgi-resident RAB33B trafficking, suppressing autophagosome initiation and contributing to intervertebral disc degeneration (IDD). Conditional knockout of Krt8 in nucleus pulposus cells aggravated load-induced IDD in vivo, while Krt8 overexpression conferred protection against overloading-induced apoptosis. Knockdown of Pkn1/Pkn2 at early IDD stages ameliorated disc degeneration.\",\n      \"method\": \"Discovery-driven phosphoproteomics; conditional Krt8 knockout mouse; Krt8 overexpression in NP cells; in vitro compressive loading; in vivo lumbar instability and tail compression models; MRI and histology; AAV-mediated gene delivery\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — specific phosphorylation site identified, in vivo genetic model, multiple orthogonal in vitro and in vivo validations\",\n      \"pmids\": [\"36897022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 promotes prostate cancer growth and metastasis by acetylating KRT8 mRNA (N4-acetylcytidine, ac4C modification), which increases KRT8 mRNA stability, elevates KRT8 protein levels, and thereby promotes epithelial-mesenchymal transition (EMT) and cell migration.\",\n      \"method\": \"NAT10 knockdown and overexpression; RNA immunoprecipitation (RIP) for ac4C-modified KRT8 mRNA; mRNA stability assays; EMT and migration assays in prostate cancer cell lines\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP validation of mRNA acetylation with functional downstream assays, single lab\",\n      \"pmids\": [\"38922788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD4 transcriptionally regulates Krt8 expression in mouse preimplantation embryos. TEAD4 knockout by base editing reduces Krt8 expression and causes developmental arrest at the morula stage with dramatic decrease in nuclear YAP in outside cells, placing Krt8 downstream of TEAD4 and upstream of Hippo/YAP signaling in trophectoderm epithelium integrity. This regulatory axis is not conserved in bovine embryos.\",\n      \"method\": \"Base editing-mediated Tead4 knockout in mouse embryos; RNA-seq of knockout embryos; immunofluorescence for KRT8, CDX2, GATA3, and YAP; comparative analysis in bovine embryos\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with RNA-seq and protein-level validation, species comparison, single lab\",\n      \"pmids\": [\"38206180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KRT8 haplotype variants are associated with cystic fibrosis disease severity and CFTR-mediated residual chloride secretion in F508del-CFTR homozygotes. One KRT8 haplotype is associated with residual chloride secretion and milder disease, suggesting that KRT8/K18 heterodimeric intermediate filaments are an essential component for proper CFTR apical membrane targeting in epithelial cells.\",\n      \"method\": \"Candidate gene association study with microsatellite and SNP markers in CF patient sibpairs stratified by disease severity and intestinal chloride secretion phenotypes\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association only, no direct mechanistic experiment, but provides in vivo human evidence for KRT8 role in CFTR trafficking\",\n      \"pmids\": [\"21548936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRF (corticotropin-releasing factor) increases intestinal epithelial permeability by upregulating CK8 expression. CK8 upregulation activates RhoA signaling, promotes actin remodeling, and decreases expression of the tight junction protein ZO-1. CK8 silencing blocked CRF-induced RhoA activation and ZO-1 downregulation but not claudin-1/occludin changes, placing CK8 as a partial mediator between CRF receptor signaling and tight junction regulation.\",\n      \"method\": \"CRF treatment of HT29 intestinal epithelial cells; CK8-silenced cells via shRNA; FITC-dextran permeability assay; transmission electron microscopy of tight junctions; immunoprecipitation for RhoA activity; immunoblotting and immunofluorescence\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — shRNA knockdown with multiple functional readouts and defined pathway placement, single lab\",\n      \"pmids\": [\"29179184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREB1 transcriptionally suppresses microRNA-186, which in turn targets KRT8 mRNA for degradation. By suppressing miR-186, CREB1 stabilizes KRT8 expression. Elevated KRT8 then increases HIF-1α expression, and HIF-1α blocks the tumor-suppressive effects of CREB1 silencing on gastric cancer cell growth, invasion, and EMT.\",\n      \"method\": \"CREB1 knockdown in gastric cancer cell lines; luciferase reporter assays for miR-186 promoter; miR-186 overexpression; KRT8 overexpression rescue experiments; HIF-1α pathway analysis; proliferation, invasion, and EMT assays\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established through multiple rescue experiments, luciferase validation, single lab\",\n      \"pmids\": [\"33061604\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT8 is a type II simple epithelial keratin that obligatorily heterodimerizes with type I partner K18 to form tetrameric assembly units and then intermediate filaments; it is required for apical membrane domain organization and microtubule anchoring in simple epithelia, is phosphorylated by PKC (at multiple sites including Ser43 by RHOA-PKN under mechanical overload) to regulate filament dynamics and autophagosome initiation, physically interacts with plectin to tether mitochondria and facilitate mitophagy, is ectopically induced in cardiomyocytes by TNF-α/NF-κB to confer cardioprotection at intercalated discs, marks a transitional stem cell state during alveolar regeneration that persists aberrantly in lung fibrosis, and modulates EMT/migration through multiple signaling axes including integrin-FAK-TGF-β/SMAD, NF-κB, RhoA-actin/tight junction, and CREB1-miR-186-HIF-1α, with its mRNA stability regulated by NAT10-mediated ac4C acetylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT8 is a type II intermediate filament protein that obligately heterodimerizes with KRT18 (or KRT19) to form cytoskeletal filaments in simple epithelia, where it organizes apical membrane polarity, modulates cell stiffness, and regulates autophagy and mitophagy. K8/K18 dimers assemble through coiled-coil interactions into tetramers and then rapidly polymerize into full-length filaments whose mechanical properties are tuned by monovalent cations and by plectin-mediated crosslinking [PMID:22085677, PMID:27489177]. KRT8 is phosphorylated by PKC, ERK1/2, and PKN1/2 at distinct sites: PKN-mediated Ser43 phosphorylation downstream of RHOA impairs RAB33B-dependent Golgi trafficking and suppresses autophagosome initiation, while ERK-mediated phosphorylation separably promotes epithelial-mesenchymal transition and facilitates autophagosome–lysosome fusion [PMID:36897022, PMID:28045574, PMID:32022439]. Loss of KRT8 in mouse enterocytes disrupts apical targeting of CFTR, syntaxin 3, and brush-border enzymes, and KRT8 interacts with plectin at the mitochondrial outer membrane to facilitate fission-mediated mitophagy, while NF-κB-driven ectopic K8/K18 expression in cardiomyocytes forms a compensatory intercalated-disc network that preserves mitochondrial integrity [PMID:11171325, PMID:33783309, PMID:26280121].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing that KRT8 is a direct in vivo substrate of protein kinase C resolved how signaling inputs regulate keratin filament dynamics in hepatocytes.\",\n      \"evidence\": \"32P metabolic labeling in primary mouse hepatocytes with TPA stimulation and PKC down-regulation\",\n      \"pmids\": [\"1283312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylation site(s) not mapped\", \"Functional consequence of PKC-mediated phosphorylation on filament assembly not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that K8 alone could stabilize endogenous K19 into filaments and promote motility/tumorigenicity — while K18 suppressed these — revealed partner-specific functional divergence within the keratin pair.\",\n      \"evidence\": \"Stable transfection of K8 or K18 into keratin-null pancreatic adenocarcinoma cells with motility and soft-agar assays\",\n      \"pmids\": [\"9152022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which K8 vs. K18 differentially affect motility not resolved\", \"Single cell line system\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"KRT8 knockout mice revealed that K8-containing filaments are essential for organizing the apical membrane domain of polarized enterocytes, including targeting of CFTR, syntaxin 3, and brush-border enzymes.\",\n      \"evidence\": \"KRT8 knockout mouse, immunofluorescence for apical markers and microtubule organization in villus enterocytes\",\n      \"pmids\": [\"11171325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between K8 filaments and apical trafficking machinery not identified\", \"Whether K8 loss affects basolateral sorting not examined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstitution of K8/K18 assembly in vitro established the obligate heterodimeric coiled-coil architecture and revealed that K8/K18 filaments polymerize faster than vimentin or desmin, providing quantitative biophysical parameters for the filament.\",\n      \"evidence\": \"Recombinant protein reconstitution, analytical ultracentrifugation, electron microscopy of assembly kinetics\",\n      \"pmids\": [\"22085677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the faster assembly kinetics compared to other IFs not resolved\", \"Post-translational modification effects on assembly not tested in vitro\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placing K8 downstream of PKP3 loss and PRL3 phosphatase upregulation showed that dephosphorylation-mediated K8 stabilization drives migration and metastasis, establishing a desmosome–phosphatase–keratin signaling axis.\",\n      \"evidence\": \"Double knockdown epistasis (PKP3 and K8 shRNA), soft agar assay, nude mouse xenograft\",\n      \"pmids\": [\"22701666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRL3 dephosphorylation of K8 not shown biochemically\", \"Specific K8 phospho-site regulated by PRL3 not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking compressive mechanical load to PKC-dependent K8 phosphorylation and disassembly in nucleus pulposus cells connected keratin dynamics to intervertebral disc degeneration pathology.\",\n      \"evidence\": \"In vitro compression model, Western blot for phospho-K8, PKC inhibitor experiments\",\n      \"pmids\": [\"24166186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific PKC isoform not identified\", \"Whether K8 filament disassembly is the cause or consequence of NP cell dysfunction not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"HDX-MS of K8/K18 at multiple assembly states mapped the structural dynamics of filament formation, showing that IF-consensus motifs mediating head-to-tail contacts become protected while linker regions remain dynamic.\",\n      \"evidence\": \"Hydrogen-deuterium exchange mass spectrometry of recombinant K8/K18 at dimer, tetramer, and filament states\",\n      \"pmids\": [\"26434626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the K8/K18 filament not achieved\", \"How phosphorylation alters these dynamic regions not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"NF-κB-driven ectopic K8/K18 expression in cardiomyocytes demonstrated that keratins can form a compensatory intercalated-disc network protecting mitochondrial integrity in desmin-deficient hearts, expanding K8 function beyond classical epithelial contexts.\",\n      \"evidence\": \"Desmin KO mice, transverse aortic constriction, electron microscopy, NF-κB inhibition, mitochondrial function assays\",\n      \"pmids\": [\"26280121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which K8/K18 localizes specifically to intercalated discs in cardiomyocytes not defined\", \"Whether this compensatory mechanism operates in human heart failure unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reconstituted K8/K18 network microrheology with plectin crosslinking and monovalent cation effects quantified the two principal mechanisms by which K8 filament networks achieve tunable mechanical stiffness in epithelia.\",\n      \"evidence\": \"In vitro K8/K18 networks with microrheology, recombinant plectin, AFM of plectin-depleted cells\",\n      \"pmids\": [\"27489177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation of K8 modulates network mechanics not tested\", \"Contribution of plectin-K8 crosslinking relative to other cytoskeletal systems in vivo not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separating phospho-K8's role in promoting EMT from total K8's cytoprotective autophagy function in RPE cells revealed that the same protein has opposing biological outcomes depending on its phosphorylation state.\",\n      \"evidence\": \"siRNA knockdown, MAPK inhibitors, autophagy inhibitors, EMT marker analysis in RPE cells\",\n      \"pmids\": [\"28045574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylation site(s) distinguishing protective vs. EMT-promoting functions not fully mapped\", \"Single tissue context (RPE)\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that phospho-K8 facilitates autophagosome–lysosome fusion during EMT refined the understanding of how K8 phosphorylation regulates autophagic flux at a specific step.\",\n      \"evidence\": \"Site-directed mutagenesis of K8 phosphorylation site, autophagy flux assay, co-localization in RPE cells and PVR patient membranes\",\n      \"pmids\": [\"32022439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular intermediary linking phospho-K8 to fusion machinery (SNAREs/Rabs) not identified\", \"Whether this mechanism operates outside RPE not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying the KRT8–plectin interaction at the mitochondrial outer membrane as a requirement for fission-mediated mitophagy established a non-cytoskeletal function for K8 in mitochondrial quality control.\",\n      \"evidence\": \"Co-IP of KRT8 with plectin and TOMM20, KRT8 knockdown, mitophagy flux assay in RPE cells under oxidative stress\",\n      \"pmids\": [\"33783309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether K8 directly contacts mitochondrial outer membrane proteins or acts solely through plectin not resolved\", \"Single cell type (RPE)\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping the RHOA→PKN1/2→KRT8-Ser43 phosphorylation axis and its impairment of RAB33B-dependent Golgi trafficking provided the most complete mechanistic pathway linking mechanical overload to autophagy suppression via keratin modification, validated in vivo.\",\n      \"evidence\": \"Conditional Krt8 KO mouse, AAV overexpression, phosphoproteomics, co-IP, RAB33B trafficking assay, Ser43 mutagenesis\",\n      \"pmids\": [\"36897022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how Ser43 phosphorylation disrupts RAB33B interaction not defined\", \"Whether this axis operates in epithelia beyond nucleus pulposus not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that NAT10-catalyzed ac4C modification of KRT8 mRNA stabilizes the transcript and increases protein levels revealed a post-transcriptional regulatory layer controlling K8 abundance and downstream EMT.\",\n      \"evidence\": \"acRIP-seq, NAT10 overexpression/knockdown, KRT8 mRNA stability assay in prostate cancer cells\",\n      \"pmids\": [\"38922788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ac4C site(s) on KRT8 mRNA not mapped to single-nucleotide resolution\", \"Whether this regulation is cancer-specific or operates in normal epithelia unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of TEAD4 as a direct transcriptional regulator of Krt8 in mouse preimplantation embryos established a developmental transcription factor upstream of K8 expression in trophectoderm specification.\",\n      \"evidence\": \"Base-editing Tead4 knockout in mouse embryos, RNA-seq, immunofluorescence for Krt8 and YAP\",\n      \"pmids\": [\"38206180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TEAD4 binds KRT8 promoter directly (ChIP) not shown\", \"Whether KRT8 loss alone is sufficient to phenocopy Tead4 KO developmental arrest not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the K8/K18 filament, the full phospho-site code linking specific kinases to distinct biological outputs, and whether K8's mitophagy and autophagy functions are generalizable beyond RPE and NP cells remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution cryo-EM or crystal structure of assembled K8/K18 filament\", \"Comprehensive phospho-site-to-function mapping across tissues not available\", \"K8 mitochondrial and autophagy roles tested in limited cell types\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 9, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 5, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [9, 16]}\n    ],\n    \"complexes\": [\n      \"K8/K18 heterodimeric intermediate filament\",\n      \"K8/K19 heterodimeric intermediate filament\"\n    ],\n    \"partners\": [\n      \"KRT18\",\n      \"KRT19\",\n      \"PLEC\",\n      \"RAB33B\",\n      \"PKN1\",\n      \"PKN2\",\n      \"NAT10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"KRT8 is a type II simple epithelial keratin that obligatorily heterodimerizes with its type I partner K18 to form tetrameric assembly units that polymerize into intermediate filaments, providing mechanical integrity and organizing the apical membrane domain and microtubule anchoring in simple epithelia [PMID:6186379, PMID:22085677, PMID:11171325]. Plectin crosslinks the K8/K18 network at filament intersection points to modulate cytoskeletal stiffness and tether mitochondria for mitophagy, while site-specific phosphorylation—by PKC under mechanical load and by RHOA–PKN at Ser43 under overloading—regulates filament dynamics, autophagosome initiation via RAB33B trafficking, and autophagosome–lysosome fusion [PMID:27489177, PMID:33783309, PMID:36897022, PMID:32022439]. KRT8 marks a transitional stem cell state during alveolar regeneration that persists aberrantly in human lung fibrosis, and ectopic TNF-α/NF-κB–driven K8/K18 expression in cardiomyocytes localizes to intercalated discs and confers cardioprotection in the absence of desmin [PMID:32678092, PMID:26280121]. In multiple carcinoma contexts, KRT8 promotes epithelial–mesenchymal transition through integrin β1–FAK–TGF-β/SMAD, NF-κB, and RhoA–tight junction signaling axes, and its mRNA stability is regulated by NAT10-mediated ac4C acetylation [PMID:27865045, PMID:29179184, PMID:38922788].\",\n  \"teleology\": [\n    {\n      \"year\": 1982,\n      \"claim\": \"Establishing KRT8 as a distinct type II simple epithelial keratin that forms obligate heteropolymeric filaments with type I partners answered the foundational question of intermediate filament subunit identity and pairing rules in simple epithelia.\",\n      \"evidence\": \"Two-dimensional gel electrophoresis and immunological characterization across normal epithelia, tumors, and cultured cells\",\n      \"pmids\": [\"6186379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly pathway of heteropolymers not yet defined\", \"In vivo requirement for K8/K18 filaments not tested genetically\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrating that PKC selectively phosphorylates K8 over K18 in hepatocytes established that K8 is a regulated signaling target rather than a passive structural scaffold, linking kinase signaling to filament reorganization.\",\n      \"evidence\": \"Metabolic radiolabeling of TPA-treated primary mouse hepatocytes with immunoprecipitation; PKC down-regulation controls\",\n      \"pmids\": [\"1283312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylation sites on K8 not mapped\", \"Functional consequence of phosphorylation on filament mechanics not quantified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"KRT8-knockout mice revealed that K8-based filaments are required for apical membrane protein retention, syntaxin 3 localization, and microtubule anchoring in intestinal enterocytes, establishing K8 as essential for epithelial polarity beyond mechanical support.\",\n      \"evidence\": \"Analysis of CK8-null mouse intestinal epithelia by immunofluorescence for apical markers, syntaxin 3, γ-tubulin, and microtubules\",\n      \"pmids\": [\"11171325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking K8 filaments to syntaxin 3 and γ-tubulin anchoring unknown\", \"Whether CFTR mistargeting in KRT8 absence directly drives disease phenotypes not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Biophysical reconstitution of K8/K18 assembly defined the tetramer as the obligate starter unit, measured filament persistence length, and showed Mg²⁺-dependent stiffening, providing the quantitative framework for understanding K8/K18 filament mechanics.\",\n      \"evidence\": \"Analytical ultracentrifugation, electron microscopy, and persistence length measurements on recombinant K8, K18, and K8/K18 mixtures\",\n      \"pmids\": [\"22085677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How post-translational modifications alter assembly kinetics and persistence length not addressed\", \"Lateral association mechanism not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"HDX-MS mapping of K8/K18 complexes across assembly states provided the first direct structural evidence that IF-consensus motifs at rod-domain termini drive filament elongation via head-to-tail contacts, resolving a long-standing structural question.\",\n      \"evidence\": \"Hydrogen-deuterium exchange mass spectrometry of recombinant K8/K18 at monomer, tetramer, and filament stages\",\n      \"pmids\": [\"26434626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution atomic structure of the assembled filament\", \"Role of individual head-to-tail contact residues not tested by mutagenesis\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that TNF-α/NF-κB induces ectopic K8/K18 in desmin-null cardiomyocytes, where the filaments localize to intercalated discs and preserve mitochondrial function, revealed an unexpected cardioprotective role for K8 outside its canonical epithelial context.\",\n      \"evidence\": \"Desmin-null and aortic constriction mouse models; immunofluorescence and EM of intercalated discs; mitochondrial assays; NF-κB conditional approaches; human failing myocardium\",\n      \"pmids\": [\"26280121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K8/K18 expression is a general cardiomyocyte stress response or specific to desmin loss unknown\", \"Molecular mechanism of K8/K18 at intercalated discs not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"In vitro reconstitution showed plectin crosslinks K8/K18 networks at intersection points without bundling and significantly increases network rigidity, validated by AFM of plectin-depleted epithelial cells, establishing plectin as a major modulator of K8/K18 cytoskeletal mechanics.\",\n      \"evidence\": \"Reconstituted K8/K18 networks with purified plectin; microrheology; AFM of detergent-extracted A431 cells with plectin siRNA\",\n      \"pmids\": [\"27489177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How plectin–K8 interaction is regulated by phosphorylation in cells not tested in this system\", \"Other crosslinkers that may cooperate with plectin not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Studies in RPE cells and gastric cancer cells converged on the principle that KRT8 phosphorylation state governs a switch between cytoprotective autophagy and pathological EMT, with ERK1/2-mediated phosphorylation promoting EMT through integrin β1–FAK–SMAD2/3 and related signaling axes.\",\n      \"evidence\": \"Pharmacological autophagy and MAPK modulation in RPE cells; KRT8 overexpression/knockdown with EMT and pathway readouts in gastric cancer cells\",\n      \"pmids\": [\"28045574\", \"27865045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise phosphorylation sites driving the autophagy-EMT switch not mapped at this stage\", \"Whether the same switch operates in normal epithelia unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Single-cell transcriptomics and lineage tracing identified a Krt8+ transitional stem cell state as a convergent intermediate during alveolar regeneration that persists aberrantly in human lung fibrosis, positioning KRT8 as a marker and potential functional participant in failed regeneration.\",\n      \"evidence\": \"Time-series scRNA-seq of bleomycin-injured mouse lungs; lineage tracing; trajectory modeling; validation in multiple injury models and human fibrosis tissue\",\n      \"pmids\": [\"32678092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KRT8 is functionally required for the transitional state or merely a marker not determined\", \"Signals that resolve versus perpetuate the Krt8+ state not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Phospho-site mutagenesis showed that phosphorylated KRT8 is required for autophagosome–lysosome fusion during TGF-β2-induced EMT, placing KRT8 phosphorylation as a direct regulator of autophagic flux rather than just filament dynamics.\",\n      \"evidence\": \"KRT8 phospho-site mutagenesis and siRNA knockdown in RPE cells; autophagy flux and EMT assays\",\n      \"pmids\": [\"32022439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the specific phosphorylation site(s) involved in fusion step not fully resolved\", \"Mechanism by which phospho-KRT8 facilitates membrane fusion unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"KRT8 physically interacts with plectin to tether mitochondria, and oxidative stress–induced KRT8 phosphorylation disrupts this interaction, impairing mitophagy and causing necrotic cell death—directly linking KRT8 phosphorylation to mitochondrial quality control.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of KRT8–plectin; siRNA knockdown; mitochondrial morphology, membrane potential, and mitophagy flux assays in RPE cells\",\n      \"pmids\": [\"33783309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site(s) governing plectin dissociation not mapped\", \"Whether this mechanism operates in epithelia beyond RPE not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of Ser43 as the RHOA–PKN phosphorylation site on KRT8 that impedes RAB33B-dependent autophagosome initiation provided the first site-specific mechanistic link between mechanical overloading, KRT8 phosphorylation, and autophagy suppression in intervertebral disc degeneration.\",\n      \"evidence\": \"Phosphoproteomics; conditional Krt8 knockout and overexpression in nucleus pulposus; in vivo lumbar instability and tail compression models; AAV-mediated gene delivery\",\n      \"pmids\": [\"36897022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser43 phosphorylation also governs the plectin–KRT8 interaction is untested\", \"Structural basis for how pSer43-KRT8 sequesters RAB33B not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"NAT10-mediated ac4C modification of KRT8 mRNA was shown to stabilize KRT8 transcript and elevate protein levels driving EMT in prostate cancer, revealing an epitranscriptomic layer of KRT8 regulation beyond transcription and phosphorylation.\",\n      \"evidence\": \"NAT10 knockdown/overexpression; RNA immunoprecipitation for ac4C-modified KRT8 mRNA; mRNA stability and EMT assays in prostate cancer cells\",\n      \"pmids\": [\"38922788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ac4C sites on KRT8 mRNA not mapped\", \"Whether ac4C modification of KRT8 mRNA occurs in normal epithelia unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TEAD4 was identified as a direct transcriptional regulator of Krt8 in mouse preimplantation embryos, positioning KRT8 downstream of Hippo signaling in trophectoderm specification, though this regulatory relationship is not conserved in bovine embryos.\",\n      \"evidence\": \"Base editing-mediated Tead4 knockout in mouse embryos; RNA-seq; immunofluorescence for KRT8, CDX2, GATA3, YAP; bovine comparison\",\n      \"pmids\": [\"38206180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TEAD4 directly binds the KRT8 promoter (ChIP) not shown\", \"Species-specific regulatory logic not explained mechanistically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: (1) the atomic-resolution structure of the assembled K8/K18 filament, (2) whether KRT8 is functionally required for—or merely marks—the transitional alveolar stem cell state in lung regeneration, and (3) the structural basis by which Ser43 phosphorylation on KRT8 interferes with RAB33B trafficking to suppress autophagosome initiation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM or crystal structure of assembled K8/K18 filament\", \"Functional requirement of KRT8 in Krt8+ transitional state not tested by conditional deletion in that lineage\", \"Structural mechanism of pSer43-KRT8 interaction with RAB33B unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 4, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 16, 18]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 22, 23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 20]}\n    ],\n    \"complexes\": [\n      \"K8/K18 intermediate filament\"\n    ],\n    \"partners\": [\n      \"KRT18\",\n      \"KRT19\",\n      \"PLEC\",\n      \"PKN1\",\n      \"RAB33B\",\n      \"NAT10\",\n      \"TEAD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}