{"gene":"HSPA13","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1994,"finding":"STCH (HSPA13) encodes a microsomal, calcium-inducible ATPase protein that is constitutively expressed, localizes to a membrane-bound microsome fraction, and demonstrates ATPase activity that is independent of peptide stimulation — unlike BiP or DnaK. The protein contains only the N-terminal ATPase domain of Hsp70 and lacks the C-terminal peptide-binding domain.","method":"Subcellular fractionation, immunofluorescence, ATPase activity assay in vitro, cDNA cloning and sequence analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ATPase assay with direct biochemical characterization, subcellular fractionation localization, multiple orthogonal methods in a single foundational study","pmids":["8131751"],"is_preprint":false},{"year":1997,"finding":"The truncated 'core ATPase' domain structure of STCH is conserved across human, rat, and C. elegans homologues, each retaining a hydrophobic signal sequence, an Hsp70 ATPase domain, and a unique C-terminal sequence (STCH-specific cluster III) that truncates the peptide-binding domain. An internal 35-aa region homologous to the Hip co-chaperone minimal ATPase-binding sequence is also conserved.","method":"Sequence analysis of conserved stop codon position, cloning of rat and C. elegans homologues, expression analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conservation of structure validated by cloning multiple orthologs and biochemical expression analysis, single lab","pmids":["9358068"],"is_preprint":false},{"year":2000,"finding":"Two ubiquitin-like (UbL) proteins, Chap1 (a Dsk2 homologue) and Chap2 (a Xenopus scythe homologue), bind to a short peptide within the ATPase domain of STCH. Chap1/Dsk2 contains a Sti1-like repeat sequence required for Stch binding. Expression of human Chap1 restored viability and suppressed G2/M arrest in dsk2Δ rad23Δ yeast.","method":"Peptide pulldown, yeast two-hybrid, genetic complementation in S. cerevisiae","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide pulldown plus genetic epistasis (complementation), single lab, two orthogonal approaches","pmids":["10675567"],"is_preprint":false},{"year":2008,"finding":"A stomach cancer-derived four-amino-acid deletion mutant of STCH (del223V-226L) in the conserved ATP-binding domain lacks ATP-binding activity. Wild-type STCH overexpression sensitizes cells to TRAIL-induced apoptosis, whereas the del223V-226L mutant does not, demonstrating that the ATPase activity is required for STCH's role in TRAIL-mediated cell death.","method":"In vitro ATP-binding assay, site-specific mutagenesis, overexpression with TRAIL treatment and cell death readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assay with mutagenesis plus functional cell death assay, single lab","pmids":["18793616"],"is_preprint":false},{"year":2013,"finding":"STCH (HSPA13) interacts with the acid/base transporters NBCe1-B (at amino acids 96–440 of NBCe1-B) and NHE1 via a specific 45-amino-acid region of STCH. Co-expression of STCH with NBCe1-B in Xenopus oocytes increased surface expression of NBCe1-B and enhanced bicarbonate conductance. STCH siRNA knockdown impaired both NBCe1-B-dependent and NHE1-dependent intracellular pH recovery from acidification.","method":"Yeast two-hybrid, Xenopus oocyte co-injection/surface expression assay, siRNA knockdown, intracellular pH measurement, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid, heterologous expression system functional assay, siRNA knockdown with pH readout, and co-IP, multiple orthogonal methods confirming same interaction and function","pmids":["23303189"],"is_preprint":false},{"year":2021,"finding":"STCH/HSPA13 binds to the ER-resident form of NKCC2 and promotes its degradation. STCH knockdown increased total NKCC2 expression, while STCH overexpression impaired NKCC2 stability and maturation in cycloheximide chase assays. STCH-mediated NKCC2 degradation involves both the proteasome and the ER-to-lysosome-associated degradation (ERLAD) pathway.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, cycloheximide chase assay, proteasome and lysosome inhibitor treatment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus gain/loss-of-function with cycloheximide chase, single lab, multiple orthogonal approaches","pmids":["33672238"],"is_preprint":false},{"year":2021,"finding":"HSPA13 binds directly to TNFR1 and RIP1, enhances TNFα-induced recruitment of RIP1 to TNFR1 (complex I), promotes downstream NF-κB transcriptional responses, and prevents RIP1 from transitioning to cytosolic complex II, thereby attenuating both apoptosis and necroptosis. Loss of HSPA13 shifts RIP1 from complex I to complex II, promoting programmed cell death.","method":"Co-immunoprecipitation (binding to TNFR1 and RIP1), HSPA13 knockout cells, NF-κB reporter assay, apoptosis/necroptosis readout","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus KO with defined cellular phenotype (apoptosis and necroptosis), single lab","pmids":["34613781"],"is_preprint":false},{"year":2022,"finding":"HSPA13 interacts primarily with the Sec61 translocon and its associated factors in the ER. Hspa13 overexpression inhibits co-translational translocation of secretory proteins (e.g., transthyretin) into the ER, causing their accumulation and aggregation in the cytosol. ATPase-inactive mutants of Hspa13 further inhibit translocation and maturation of secretory proteins. HSPA13 knockout destabilizes proteostasis and increases sensitivity to ER disruption.","method":"Mass spectrometry interactome (Sec61 co-purification), overexpression and ATPase-inactive mutagenesis with translocation/maturation assays, HSPA13 knockout with ER stress sensitivity assay, aggregation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS-validated interaction with Sec61, ATPase-dead mutagenesis with functional translocation assay, KO phenotype, multiple orthogonal methods in single study","pmids":["36244454"],"is_preprint":false},{"year":2020,"finding":"Hspa13 interacts with BCAP31 (Bcap31) in the ER and positively regulates protein transport from the ER to the cytosol. B cell-specific conditional knockout of Hspa13 (CD19cre-mediated) reduced plasmablast and plasma cell numbers, antibody production (including class-switched and somatically hypermutated antibodies), and affinity maturation.","method":"Co-immunoprecipitation (Bcap31 interaction), B cell-specific conditional knockout mouse, LPS stimulation, immunization with SRBCs and NP-hapten, ELISA","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined interactor plus cell-type-specific KO with defined immunological phenotype, single lab","pmids":["32547538"],"is_preprint":false},{"year":2023,"finding":"HSPA13 interacts with TANK protein and inhibits TANK's ubiquitination and degradation, thereby stabilizing TANK in hepatocellular carcinoma cells. Knockdown of HSPA13 reduced HCC cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion readout","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay plus loss-of-function phenotype, single lab","pmids":["38062023"],"is_preprint":false},{"year":2023,"finding":"HSPA13 interacts with RIG-I and upregulates RIG-I expression during dengue virus infection, promoting IFN-β production and ISG expression. HSPA13 also interacts with ASC to enhance NLRP3 inflammasome activation and IL-1β secretion during DENV infection.","method":"Co-immunoprecipitation (RIG-I and ASC binding), overexpression/knockdown with IFN-β, ISG, and IL-1β readout, viral replication assay","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for two distinct interactors plus functional KD/OE with cytokine and viral replication readouts, single lab","pmids":["37776769"],"is_preprint":false},{"year":2024,"finding":"Hspa13 binds directly to the IL-10 promoter (via TATA or CAAT box elements) and activates IL-10 transcription in the nucleus of B cells. Hspa13 knockout or knockdown in B cells impairs IL-10 production and reduces IL-10-dependent Treg differentiation.","method":"ChIP or promoter binding assay, siRNA knockdown/knockout, IL-10 reporter or ELISA, Treg differentiation assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct promoter binding assay plus KO functional readout (IL-10 and Treg), single lab","pmids":["39737854"],"is_preprint":false},{"year":2024,"finding":"HSPA13 knockdown inhibits TGFβ1-induced EMT and migration in RPE cells by suppressing PI3K/Akt phosphorylation. TGFβ1 treatment increases intracellular Ca2+ levels, which upregulates HSPA13 expression upstream of PI3K/Akt signaling.","method":"siRNA knockdown, Western blot for PI3K/Akt phosphorylation, intracellular Ca2+ measurement, wound healing assay, RNA-seq, rat PVR model with in vivo knockdown","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined signaling pathway readout (PI3K/Akt phosphorylation) plus in vivo model, single lab, multiple methods","pmids":["39226050"],"is_preprint":false},{"year":2024,"finding":"YTHDF3, an m6A reader protein, enhances degradation of HSPA13 mRNA through phase separation and recruitment of DDX6, resulting in reduced HSPA13 protein levels and downstream downregulation of PD-L1 in clear cell renal cell carcinoma cells.","method":"mRNA degradation assay, YTHDF3 overexpression/mutant (phase separation-deficient), HSPA13 overexpression rescue experiments, DDX6 co-IP","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mRNA-level regulation via m6A reader with rescue experiment, functional phase-separation mutant, single lab","pmids":["38811341"],"is_preprint":false}],"current_model":"HSPA13 (STCH) is a constitutively expressed, calcium-inducible, microsome/ER-localized Hsp70-family ATPase that contains only the N-terminal ATPase domain (lacking the C-terminal peptide-binding domain); its ATPase activity, which is peptide-stimulation-independent, is required for its functions, which include regulating protein translocation through the Sec61 translocon, interacting with and modulating membrane transporters (NBCe1-B, NHE1, NKCC2) and signaling proteins (TNFR1/RIP1, TANK, RIG-I, ASC), and thereby influencing ER proteostasis, intracellular pH recovery, TNFα/NF-κB versus cell-death pathway selection, innate immune signaling, and plasma cell antibody secretion."},"narrative":{"mechanistic_narrative":"HSPA13 (STCH) is a constitutively expressed, calcium-inducible Hsp70-family ATPase that localizes to the microsome/ER membrane and, uniquely among Hsp70 proteins, contains only the N-terminal ATPase domain while lacking the C-terminal peptide-binding domain — consequently its ATPase activity is independent of peptide stimulation [PMID:8131751]. This truncated 'core ATPase' architecture, together with a conserved Hip-like co-chaperone-binding region, is preserved across human, rat, and C. elegans homologues [PMID:9358068], and its ATPase activity is functionally essential: ATP-binding-deficient mutants fail to recapitulate its activities [PMID:18793616, PMID:36244454]. At the ER membrane HSPA13 acts on the secretory pathway by interacting with the Sec61 translocon, where its overexpression — exacerbated by ATPase-inactive mutants — impairs co-translational translocation and maturation of secretory proteins, causing cytosolic aggregation, while its loss destabilizes ER proteostasis [PMID:36244454]. Through this proteostatic role it governs the surface delivery, stability, and degradation of membrane transporters, promoting NBCe1-B/NHE1-dependent intracellular pH recovery [PMID:23303189] and routing ER-resident NKCC2 to proteasomal and ER-to-lysosome-associated degradation [PMID:33672238]. HSPA13 additionally functions as a signaling modulator that influences cell-fate and immune outcomes: it binds TNFR1 and RIP1 to stabilize complex I and bias TNFα signaling toward NF-κB and away from apoptosis/necroptosis [PMID:34613781], and it engages innate-immune and inflammasome components (RIG-I, ASC) to amplify antiviral and IL-1β responses [PMID:37776769]. In B cells it supports plasma cell differentiation and antibody secretion via interaction with BCAP31-dependent ER-to-cytosol transport [PMID:32547538] and activates IL-10 transcription through direct promoter binding [PMID:39737854].","teleology":[{"year":1994,"claim":"Established HSPA13/STCH as a distinct Hsp70 family member by showing it is a microsomal, calcium-inducible ATPase whose activity, unlike BiP/DnaK, is peptide-independent and which structurally retains only the N-terminal ATPase domain.","evidence":"Subcellular fractionation, immunofluorescence, in vitro ATPase assay, and cDNA cloning","pmids":["8131751"],"confidence":"High","gaps":["Physiological substrates or partners of the ATPase activity not identified","Functional consequence of lacking the peptide-binding domain unresolved"]},{"year":1997,"claim":"Demonstrated the truncated core-ATPase architecture and a conserved Hip-like internal sequence are evolutionarily conserved, implying the domain truncation is functionally selected rather than an artifact.","evidence":"Sequence analysis and cloning of rat and C. elegans orthologs with expression analysis","pmids":["9358068"],"confidence":"Medium","gaps":["No direct demonstration that the Hip-like region binds Hip in vivo","Functional role of the unique C-terminal cluster III undefined"]},{"year":2000,"claim":"Identified ubiquitin-like proteins Chap1/Dsk2 and Chap2/scythe as binders of the STCH ATPase domain, linking it to ubiquitin-pathway co-chaperones.","evidence":"Peptide pulldown, yeast two-hybrid, and genetic complementation in S. cerevisiae","pmids":["10675567"],"confidence":"Medium","gaps":["Biological consequence of these interactions in mammalian cells not established","Single-lab finding without reciprocal validation in human cells"]},{"year":2008,"claim":"Showed ATPase activity is mechanistically required for STCH function by demonstrating an ATP-binding-deficient deletion mutant fails to sensitize cells to TRAIL-induced apoptosis.","evidence":"In vitro ATP-binding assay, site-specific mutagenesis, and overexpression with TRAIL cell-death readout","pmids":["18793616"],"confidence":"Medium","gaps":["Molecular intermediates linking STCH to TRAIL apoptosis not defined","Overexpression context only; endogenous relevance unclear"]},{"year":2013,"claim":"Defined a transporter-regulatory role by showing STCH binds NBCe1-B and NHE1 and is required for their surface delivery and intracellular pH recovery from acidification.","evidence":"Yeast two-hybrid, Xenopus oocyte surface expression, siRNA knockdown with pH measurement, and co-IP","pmids":["23303189"],"confidence":"High","gaps":["Whether ATPase activity is required for transporter trafficking not tested","Mechanism of surface delivery (chaperoning vs. translocation) unresolved"]},{"year":2020,"claim":"Connected ER-to-cytosol protein transport to humoral immunity by showing Hspa13 interacts with BCAP31 and is required for plasma cell differentiation, antibody production, and affinity maturation.","evidence":"Co-IP and B cell-specific conditional knockout mouse with immunization and ELISA readouts","pmids":["32547538"],"confidence":"Medium","gaps":["Direct cargo transported via the BCAP31 axis not identified","Whether ATPase activity drives transport not tested"]},{"year":2021,"claim":"Revealed a cell-fate switch function: HSPA13 binds TNFR1 and RIP1 to stabilize complex I, promoting NF-κB signaling and preventing RIP1 transition to death-inducing complex II.","evidence":"Reciprocal Co-IP, HSPA13 knockout cells, NF-κB reporter, and apoptosis/necroptosis assays","pmids":["34613781"],"confidence":"Medium","gaps":["Whether HSPA13 acts catalytically or as a scaffold at complex I unclear","Single-lab finding"]},{"year":2021,"claim":"Extended transporter regulation to degradation by showing HSPA13 binds ER-resident NKCC2 and promotes its turnover via proteasome and ERLAD pathways.","evidence":"Co-IP, knockdown/overexpression, cycloheximide chase, and proteasome/lysosome inhibitor treatment","pmids":["33672238"],"confidence":"Medium","gaps":["How HSPA13 selects substrates for degradation vs. delivery unknown","Direct involvement of ATPase activity not tested"]},{"year":2022,"claim":"Established the core ER mechanism: HSPA13 interacts with the Sec61 translocon and, in an ATPase-dependent manner, modulates co-translational translocation and maturation of secretory proteins, with loss destabilizing proteostasis.","evidence":"Mass-spectrometry interactome, ATPase-inactive mutagenesis with translocation assays, and knockout ER-stress sensitivity assay","pmids":["36244454"],"confidence":"High","gaps":["Whether HSPA13 facilitates or gates translocation under physiological conditions unresolved","Structural basis of Sec61 engagement unknown"]},{"year":2023,"claim":"Documented additional signaling roles in cancer and antiviral immunity: HSPA13 stabilizes TANK by inhibiting its ubiquitination and engages RIG-I and ASC to enhance type I IFN, ISG, and IL-1β responses.","evidence":"Co-IP, ubiquitination assays, and knockdown/overexpression with proliferation, cytokine, and viral replication readouts","pmids":["38062023","37776769"],"confidence":"Medium","gaps":["Mechanism by which HSPA13 protects partners from ubiquitination undefined","Direct vs. indirect engagement of inflammasome components unclear"]},{"year":2024,"claim":"Identified nuclear and regulatory functions: Hspa13 binds the IL-10 promoter to activate transcription and Treg differentiation, while a TGFβ1/Ca2+/PI3K-Akt axis drives EMT, and YTHDF3/m6A controls HSPA13 mRNA stability and downstream PD-L1.","evidence":"Promoter binding/ChIP, knockout IL-10/Treg assays, PI3K-Akt phosphorylation and in vivo PVR model, and m6A mRNA degradation/rescue assays","pmids":["39737854","39226050","38811341"],"confidence":"Medium","gaps":["How a membrane ATPase localizes to the nucleus to bind DNA unexplained","Relationship between ER and transcriptional functions unresolved"]},{"year":null,"claim":"How a single truncated, peptide-independent ATPase coordinates its diverse ER-translocon, transporter, signaling, and transcriptional activities through a unified molecular mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of HSPA13 bound to Sec61 or transporters","No defined co-chaperone/nucleotide-exchange partner explaining ATPase cycling","Mechanism reconciling cytosolic/ER and nuclear localizations not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5,7,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,10,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,12]}],"complexes":["Sec61 translocon (associated)","TNFR1 complex I"],"partners":["SEC61","NBCE1-B (SLC4A4)","NHE1 (SLC9A1)","NKCC2 (SLC12A1)","TNFR1","RIPK1","BCAP31","TANK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48723","full_name":"Heat shock 70 kDa protein 13","aliases":["Heat shock protein family A member 13","Microsomal stress-70 protein ATPase core","Stress-70 protein chaperone microsome-associated 60 kDa protein"],"length_aa":471,"mass_kda":51.9,"function":"Has peptide-independent ATPase activity","subcellular_location":"Microsome; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P48723/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSPA13","classification":"Not Classified","n_dependent_lines":172,"n_total_lines":1208,"dependency_fraction":0.1423841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HSPA13","total_profiled":1310},"omim":[{"mim_id":"601100","title":"HEAT SHOCK 70-KD PROTEIN 13; HSPA13","url":"https://www.omim.org/entry/601100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HSPA13"},"hgnc":{"alias_symbol":[],"prev_symbol":["STCH"]},"alphafold":{"accession":"P48723","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48723","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48723-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48723-F1-predicted_aligned_error_v6.png","plddt_mean":87.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSPA13","jax_strain_url":"https://www.jax.org/strain/search?query=HSPA13"},"sequence":{"accession":"P48723","fasta_url":"https://rest.uniprot.org/uniprotkb/P48723.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48723/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48723"}},"corpus_meta":[{"pmid":"10675567","id":"PMC_10675567","title":"A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch.","date":"2000","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10675567","citation_count":88,"is_preprint":false},{"pmid":"8131751","id":"PMC_8131751","title":"Stch encodes the 'ATPase core' of a microsomal stress 70 protein.","date":"1994","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8131751","citation_count":49,"is_preprint":false},{"pmid":"25803843","id":"PMC_25803843","title":"Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25803843","citation_count":28,"is_preprint":false},{"pmid":"23303189","id":"PMC_23303189","title":"Chaperone stress 70 protein (STCH) binds and regulates two acid/base transporters NBCe1-B and NHE1.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23303189","citation_count":23,"is_preprint":false},{"pmid":"38811341","id":"PMC_38811341","title":"YTHDF3 phase separation regulates HSPA13-dependent clear cell renal cell carcinoma development and immune evasion.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/38811341","citation_count":17,"is_preprint":false},{"pmid":"22869728","id":"PMC_22869728","title":"Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22869728","citation_count":17,"is_preprint":false},{"pmid":"9358068","id":"PMC_9358068","title":"A 'core ATPase', Hsp70-like structure is conserved in human, rat, and C. elegans STCH proteins.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9358068","citation_count":17,"is_preprint":false},{"pmid":"36244454","id":"PMC_36244454","title":"Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36244454","citation_count":14,"is_preprint":false},{"pmid":"33672238","id":"PMC_33672238","title":"Differential Effects of STCH and Stress-Inducible Hsp70 on the Stability and Maturation of NKCC2.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33672238","citation_count":13,"is_preprint":false},{"pmid":"18793616","id":"PMC_18793616","title":"Stomach cancer-derived del223V-226L mutation of the STCH gene causes loss of sensitization to TRAIL-mediated apoptosis.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18793616","citation_count":13,"is_preprint":false},{"pmid":"34613781","id":"PMC_34613781","title":"HSPA13 facilitates NF-κB-mediated transcription and attenuates cell death responses in TNFα signaling.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34613781","citation_count":12,"is_preprint":false},{"pmid":"32547538","id":"PMC_32547538","title":"Hspa13 Promotes Plasma Cell Production and Antibody Secretion.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32547538","citation_count":11,"is_preprint":false},{"pmid":"16087163","id":"PMC_16087163","title":"A genetic variant in the gene encoding the stress70 protein chaperone family member STCH is associated with gastric cancer in the Japanese population.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16087163","citation_count":10,"is_preprint":false},{"pmid":"38062023","id":"PMC_38062023","title":"Heat shock protein HSPA13 promotes hepatocellular carcinoma progression by stabilizing TANK.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38062023","citation_count":7,"is_preprint":false},{"pmid":"37776769","id":"PMC_37776769","title":"HSPA13 modulates type I interferon antiviral pathway and NLRP3 inflammasome to restrict dengue virus infection in macrophages.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37776769","citation_count":5,"is_preprint":false},{"pmid":"39226050","id":"PMC_39226050","title":"Knockdown of HSPA13 Inhibits TGFβ1-Induced Epithelial-Mesenchymal Transition of RPE by Suppressing the PI3K/Akt Signaling Pathway.","date":"2024","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/39226050","citation_count":5,"is_preprint":false},{"pmid":"39737854","id":"PMC_39737854","title":"Hspa13 Deficiency Impaired Marginal Zone B Cells Regulatory Function and Contributed to Lupus Pathogenesis.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39737854","citation_count":3,"is_preprint":false},{"pmid":"34837777","id":"PMC_34837777","title":"Single-cell atlas of splenocytes reveals a critical role of a novel plasma cell‒specific marker Hspa13 in antibody class-switching recombination and somatic hypermutation.","date":"2021","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34837777","citation_count":3,"is_preprint":false},{"pmid":"40959651","id":"PMC_40959651","title":"HSPA13 gene and microRNA-155: relationship between Down syndrome and Alzheimer's disease.","date":"2025","source":"Dementia & neuropsychologia","url":"https://pubmed.ncbi.nlm.nih.gov/40959651","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.30.25337017","title":"Surface Markers on Supermeres Outperform Extracellular Vesicles in Cancer Diagnosis","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.30.25337017","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11703,"output_tokens":3748,"usd":0.045664,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11406,"output_tokens":4124,"usd":0.080065,"stage2_stop_reason":"end_turn"},"total_usd":0.125729,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"STCH (HSPA13) encodes a microsomal, calcium-inducible ATPase protein that is constitutively expressed, localizes to a membrane-bound microsome fraction, and demonstrates ATPase activity that is independent of peptide stimulation — unlike BiP or DnaK. The protein contains only the N-terminal ATPase domain of Hsp70 and lacks the C-terminal peptide-binding domain.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, ATPase activity assay in vitro, cDNA cloning and sequence analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ATPase assay with direct biochemical characterization, subcellular fractionation localization, multiple orthogonal methods in a single foundational study\",\n      \"pmids\": [\"8131751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The truncated 'core ATPase' domain structure of STCH is conserved across human, rat, and C. elegans homologues, each retaining a hydrophobic signal sequence, an Hsp70 ATPase domain, and a unique C-terminal sequence (STCH-specific cluster III) that truncates the peptide-binding domain. An internal 35-aa region homologous to the Hip co-chaperone minimal ATPase-binding sequence is also conserved.\",\n      \"method\": \"Sequence analysis of conserved stop codon position, cloning of rat and C. elegans homologues, expression analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conservation of structure validated by cloning multiple orthologs and biochemical expression analysis, single lab\",\n      \"pmids\": [\"9358068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Two ubiquitin-like (UbL) proteins, Chap1 (a Dsk2 homologue) and Chap2 (a Xenopus scythe homologue), bind to a short peptide within the ATPase domain of STCH. Chap1/Dsk2 contains a Sti1-like repeat sequence required for Stch binding. Expression of human Chap1 restored viability and suppressed G2/M arrest in dsk2Δ rad23Δ yeast.\",\n      \"method\": \"Peptide pulldown, yeast two-hybrid, genetic complementation in S. cerevisiae\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide pulldown plus genetic epistasis (complementation), single lab, two orthogonal approaches\",\n      \"pmids\": [\"10675567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A stomach cancer-derived four-amino-acid deletion mutant of STCH (del223V-226L) in the conserved ATP-binding domain lacks ATP-binding activity. Wild-type STCH overexpression sensitizes cells to TRAIL-induced apoptosis, whereas the del223V-226L mutant does not, demonstrating that the ATPase activity is required for STCH's role in TRAIL-mediated cell death.\",\n      \"method\": \"In vitro ATP-binding assay, site-specific mutagenesis, overexpression with TRAIL treatment and cell death readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assay with mutagenesis plus functional cell death assay, single lab\",\n      \"pmids\": [\"18793616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STCH (HSPA13) interacts with the acid/base transporters NBCe1-B (at amino acids 96–440 of NBCe1-B) and NHE1 via a specific 45-amino-acid region of STCH. Co-expression of STCH with NBCe1-B in Xenopus oocytes increased surface expression of NBCe1-B and enhanced bicarbonate conductance. STCH siRNA knockdown impaired both NBCe1-B-dependent and NHE1-dependent intracellular pH recovery from acidification.\",\n      \"method\": \"Yeast two-hybrid, Xenopus oocyte co-injection/surface expression assay, siRNA knockdown, intracellular pH measurement, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid, heterologous expression system functional assay, siRNA knockdown with pH readout, and co-IP, multiple orthogonal methods confirming same interaction and function\",\n      \"pmids\": [\"23303189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STCH/HSPA13 binds to the ER-resident form of NKCC2 and promotes its degradation. STCH knockdown increased total NKCC2 expression, while STCH overexpression impaired NKCC2 stability and maturation in cycloheximide chase assays. STCH-mediated NKCC2 degradation involves both the proteasome and the ER-to-lysosome-associated degradation (ERLAD) pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, cycloheximide chase assay, proteasome and lysosome inhibitor treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus gain/loss-of-function with cycloheximide chase, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"33672238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSPA13 binds directly to TNFR1 and RIP1, enhances TNFα-induced recruitment of RIP1 to TNFR1 (complex I), promotes downstream NF-κB transcriptional responses, and prevents RIP1 from transitioning to cytosolic complex II, thereby attenuating both apoptosis and necroptosis. Loss of HSPA13 shifts RIP1 from complex I to complex II, promoting programmed cell death.\",\n      \"method\": \"Co-immunoprecipitation (binding to TNFR1 and RIP1), HSPA13 knockout cells, NF-κB reporter assay, apoptosis/necroptosis readout\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus KO with defined cellular phenotype (apoptosis and necroptosis), single lab\",\n      \"pmids\": [\"34613781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSPA13 interacts primarily with the Sec61 translocon and its associated factors in the ER. Hspa13 overexpression inhibits co-translational translocation of secretory proteins (e.g., transthyretin) into the ER, causing their accumulation and aggregation in the cytosol. ATPase-inactive mutants of Hspa13 further inhibit translocation and maturation of secretory proteins. HSPA13 knockout destabilizes proteostasis and increases sensitivity to ER disruption.\",\n      \"method\": \"Mass spectrometry interactome (Sec61 co-purification), overexpression and ATPase-inactive mutagenesis with translocation/maturation assays, HSPA13 knockout with ER stress sensitivity assay, aggregation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS-validated interaction with Sec61, ATPase-dead mutagenesis with functional translocation assay, KO phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36244454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hspa13 interacts with BCAP31 (Bcap31) in the ER and positively regulates protein transport from the ER to the cytosol. B cell-specific conditional knockout of Hspa13 (CD19cre-mediated) reduced plasmablast and plasma cell numbers, antibody production (including class-switched and somatically hypermutated antibodies), and affinity maturation.\",\n      \"method\": \"Co-immunoprecipitation (Bcap31 interaction), B cell-specific conditional knockout mouse, LPS stimulation, immunization with SRBCs and NP-hapten, ELISA\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined interactor plus cell-type-specific KO with defined immunological phenotype, single lab\",\n      \"pmids\": [\"32547538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSPA13 interacts with TANK protein and inhibits TANK's ubiquitination and degradation, thereby stabilizing TANK in hepatocellular carcinoma cells. Knockdown of HSPA13 reduced HCC cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion readout\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay plus loss-of-function phenotype, single lab\",\n      \"pmids\": [\"38062023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSPA13 interacts with RIG-I and upregulates RIG-I expression during dengue virus infection, promoting IFN-β production and ISG expression. HSPA13 also interacts with ASC to enhance NLRP3 inflammasome activation and IL-1β secretion during DENV infection.\",\n      \"method\": \"Co-immunoprecipitation (RIG-I and ASC binding), overexpression/knockdown with IFN-β, ISG, and IL-1β readout, viral replication assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for two distinct interactors plus functional KD/OE with cytokine and viral replication readouts, single lab\",\n      \"pmids\": [\"37776769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hspa13 binds directly to the IL-10 promoter (via TATA or CAAT box elements) and activates IL-10 transcription in the nucleus of B cells. Hspa13 knockout or knockdown in B cells impairs IL-10 production and reduces IL-10-dependent Treg differentiation.\",\n      \"method\": \"ChIP or promoter binding assay, siRNA knockdown/knockout, IL-10 reporter or ELISA, Treg differentiation assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct promoter binding assay plus KO functional readout (IL-10 and Treg), single lab\",\n      \"pmids\": [\"39737854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA13 knockdown inhibits TGFβ1-induced EMT and migration in RPE cells by suppressing PI3K/Akt phosphorylation. TGFβ1 treatment increases intracellular Ca2+ levels, which upregulates HSPA13 expression upstream of PI3K/Akt signaling.\",\n      \"method\": \"siRNA knockdown, Western blot for PI3K/Akt phosphorylation, intracellular Ca2+ measurement, wound healing assay, RNA-seq, rat PVR model with in vivo knockdown\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined signaling pathway readout (PI3K/Akt phosphorylation) plus in vivo model, single lab, multiple methods\",\n      \"pmids\": [\"39226050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF3, an m6A reader protein, enhances degradation of HSPA13 mRNA through phase separation and recruitment of DDX6, resulting in reduced HSPA13 protein levels and downstream downregulation of PD-L1 in clear cell renal cell carcinoma cells.\",\n      \"method\": \"mRNA degradation assay, YTHDF3 overexpression/mutant (phase separation-deficient), HSPA13 overexpression rescue experiments, DDX6 co-IP\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mRNA-level regulation via m6A reader with rescue experiment, functional phase-separation mutant, single lab\",\n      \"pmids\": [\"38811341\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSPA13 (STCH) is a constitutively expressed, calcium-inducible, microsome/ER-localized Hsp70-family ATPase that contains only the N-terminal ATPase domain (lacking the C-terminal peptide-binding domain); its ATPase activity, which is peptide-stimulation-independent, is required for its functions, which include regulating protein translocation through the Sec61 translocon, interacting with and modulating membrane transporters (NBCe1-B, NHE1, NKCC2) and signaling proteins (TNFR1/RIP1, TANK, RIG-I, ASC), and thereby influencing ER proteostasis, intracellular pH recovery, TNFα/NF-κB versus cell-death pathway selection, innate immune signaling, and plasma cell antibody secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HSPA13 (STCH) is a constitutively expressed, calcium-inducible Hsp70-family ATPase that localizes to the microsome/ER membrane and, uniquely among Hsp70 proteins, contains only the N-terminal ATPase domain while lacking the C-terminal peptide-binding domain — consequently its ATPase activity is independent of peptide stimulation [#0]. This truncated 'core ATPase' architecture, together with a conserved Hip-like co-chaperone-binding region, is preserved across human, rat, and C. elegans homologues [#1], and its ATPase activity is functionally essential: ATP-binding-deficient mutants fail to recapitulate its activities [#3, #7]. At the ER membrane HSPA13 acts on the secretory pathway by interacting with the Sec61 translocon, where its overexpression — exacerbated by ATPase-inactive mutants — impairs co-translational translocation and maturation of secretory proteins, causing cytosolic aggregation, while its loss destabilizes ER proteostasis [#7]. Through this proteostatic role it governs the surface delivery, stability, and degradation of membrane transporters, promoting NBCe1-B/NHE1-dependent intracellular pH recovery [#4] and routing ER-resident NKCC2 to proteasomal and ER-to-lysosome-associated degradation [#5]. HSPA13 additionally functions as a signaling modulator that influences cell-fate and immune outcomes: it binds TNFR1 and RIP1 to stabilize complex I and bias TNFα signaling toward NF-κB and away from apoptosis/necroptosis [#6], and it engages innate-immune and inflammasome components (RIG-I, ASC) to amplify antiviral and IL-1β responses [#10]. In B cells it supports plasma cell differentiation and antibody secretion via interaction with BCAP31-dependent ER-to-cytosol transport [#8] and activates IL-10 transcription through direct promoter binding [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established HSPA13/STCH as a distinct Hsp70 family member by showing it is a microsomal, calcium-inducible ATPase whose activity, unlike BiP/DnaK, is peptide-independent and which structurally retains only the N-terminal ATPase domain.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, in vitro ATPase assay, and cDNA cloning\",\n      \"pmids\": [\"8131751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates or partners of the ATPase activity not identified\", \"Functional consequence of lacking the peptide-binding domain unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated the truncated core-ATPase architecture and a conserved Hip-like internal sequence are evolutionarily conserved, implying the domain truncation is functionally selected rather than an artifact.\",\n      \"evidence\": \"Sequence analysis and cloning of rat and C. elegans orthologs with expression analysis\",\n      \"pmids\": [\"9358068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration that the Hip-like region binds Hip in vivo\", \"Functional role of the unique C-terminal cluster III undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified ubiquitin-like proteins Chap1/Dsk2 and Chap2/scythe as binders of the STCH ATPase domain, linking it to ubiquitin-pathway co-chaperones.\",\n      \"evidence\": \"Peptide pulldown, yeast two-hybrid, and genetic complementation in S. cerevisiae\",\n      \"pmids\": [\"10675567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biological consequence of these interactions in mammalian cells not established\", \"Single-lab finding without reciprocal validation in human cells\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed ATPase activity is mechanistically required for STCH function by demonstrating an ATP-binding-deficient deletion mutant fails to sensitize cells to TRAIL-induced apoptosis.\",\n      \"evidence\": \"In vitro ATP-binding assay, site-specific mutagenesis, and overexpression with TRAIL cell-death readout\",\n      \"pmids\": [\"18793616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular intermediates linking STCH to TRAIL apoptosis not defined\", \"Overexpression context only; endogenous relevance unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a transporter-regulatory role by showing STCH binds NBCe1-B and NHE1 and is required for their surface delivery and intracellular pH recovery from acidification.\",\n      \"evidence\": \"Yeast two-hybrid, Xenopus oocyte surface expression, siRNA knockdown with pH measurement, and co-IP\",\n      \"pmids\": [\"23303189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATPase activity is required for transporter trafficking not tested\", \"Mechanism of surface delivery (chaperoning vs. translocation) unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected ER-to-cytosol protein transport to humoral immunity by showing Hspa13 interacts with BCAP31 and is required for plasma cell differentiation, antibody production, and affinity maturation.\",\n      \"evidence\": \"Co-IP and B cell-specific conditional knockout mouse with immunization and ELISA readouts\",\n      \"pmids\": [\"32547538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo transported via the BCAP31 axis not identified\", \"Whether ATPase activity drives transport not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a cell-fate switch function: HSPA13 binds TNFR1 and RIP1 to stabilize complex I, promoting NF-κB signaling and preventing RIP1 transition to death-inducing complex II.\",\n      \"evidence\": \"Reciprocal Co-IP, HSPA13 knockout cells, NF-κB reporter, and apoptosis/necroptosis assays\",\n      \"pmids\": [\"34613781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HSPA13 acts catalytically or as a scaffold at complex I unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended transporter regulation to degradation by showing HSPA13 binds ER-resident NKCC2 and promotes its turnover via proteasome and ERLAD pathways.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, cycloheximide chase, and proteasome/lysosome inhibitor treatment\",\n      \"pmids\": [\"33672238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPA13 selects substrates for degradation vs. delivery unknown\", \"Direct involvement of ATPase activity not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the core ER mechanism: HSPA13 interacts with the Sec61 translocon and, in an ATPase-dependent manner, modulates co-translational translocation and maturation of secretory proteins, with loss destabilizing proteostasis.\",\n      \"evidence\": \"Mass-spectrometry interactome, ATPase-inactive mutagenesis with translocation assays, and knockout ER-stress sensitivity assay\",\n      \"pmids\": [\"36244454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSPA13 facilitates or gates translocation under physiological conditions unresolved\", \"Structural basis of Sec61 engagement unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Documented additional signaling roles in cancer and antiviral immunity: HSPA13 stabilizes TANK by inhibiting its ubiquitination and engages RIG-I and ASC to enhance type I IFN, ISG, and IL-1β responses.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and knockdown/overexpression with proliferation, cytokine, and viral replication readouts\",\n      \"pmids\": [\"38062023\", \"37776769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HSPA13 protects partners from ubiquitination undefined\", \"Direct vs. indirect engagement of inflammasome components unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified nuclear and regulatory functions: Hspa13 binds the IL-10 promoter to activate transcription and Treg differentiation, while a TGFβ1/Ca2+/PI3K-Akt axis drives EMT, and YTHDF3/m6A controls HSPA13 mRNA stability and downstream PD-L1.\",\n      \"evidence\": \"Promoter binding/ChIP, knockout IL-10/Treg assays, PI3K-Akt phosphorylation and in vivo PVR model, and m6A mRNA degradation/rescue assays\",\n      \"pmids\": [\"39737854\", \"39226050\", \"38811341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a membrane ATPase localizes to the nucleus to bind DNA unexplained\", \"Relationship between ER and transcriptional functions unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single truncated, peptide-independent ATPase coordinates its diverse ER-translocon, transporter, signaling, and transcriptional activities through a unified molecular mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HSPA13 bound to Sec61 or transporters\", \"No defined co-chaperone/nucleotide-exchange partner explaining ATPase cycling\", \"Mechanism reconciling cytosolic/ER and nuclear localizations not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5, 7, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 10, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [\"Sec61 translocon (associated)\", \"TNFR1 complex I\"],\n    \"partners\": [\"SEC61\", \"NBCe1-B (SLC4A4)\", \"NHE1 (SLC9A1)\", \"NKCC2 (SLC12A1)\", \"TNFR1\", \"RIPK1\", \"BCAP31\", \"TANK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}