{"gene":"HRC","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"HRC binds directly to triadin (an integral membrane protein of the sarcoplasmic reticulum) in the SR lumen, as demonstrated by co-immunoprecipitation. The histidine-rich acidic repeats of HRC were identified as responsible for this binding via fusion protein binding assay. The HRC-binding domain of triadin was localized to the lumenal region containing the KEKE motif. Importantly, the interaction is Ca2+-sensitive.","method":"Co-immunoprecipitation and fusion protein binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with domain mapping, single lab but two orthogonal methods","pmids":["11504710"],"is_preprint":false},{"year":1999,"finding":"HRC exists as a multimeric complex (likely larger than a pentamer) under physiological conditions in the SR lumen; at higher Ca2+ concentrations the complex dissociates into dimers or trimers. HRC resides in the lumen of the SR (not the membrane), confirmed by tryptic digestion and biotinylation of SR vesicles.","method":"Native gel electrophoresis, tryptic digestion of SR vesicles, biotinylation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods in one study, single lab","pmids":["10512736"],"is_preprint":false},{"year":2003,"finding":"Overexpression of HRC in rat neonatal cardiomyocytes increases SR Ca2+ storage capacity: caffeine-induced and depolarization-induced Ca2+ release were significantly increased, and SR Ca2+ content (measured by cyclopiazonic acid depletion) remained elevated. Ryanodine receptor density and binding kinetics were not significantly altered, implicating HRC primarily in SR Ca2+ buffering.","method":"Overexpression in neonatal cardiomyocytes, Ca2+ imaging, ryanodine binding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular assay with multiple Ca2+ readouts, single lab","pmids":["12480542"],"is_preprint":false},{"year":2004,"finding":"HRC gene expression in cardiac, skeletal, and arterial smooth muscle is directly controlled by MEF2 transcription factor. A conserved MEF2 binding site in the HRC enhancer was shown to be required for expression in all three muscle lineages in transgenic mice. The HRC enhancer lacks CArG motifs and is not activated by SRF, making HRC the first MEF2-dependent, CArG-independent SR gene transcriptional target in smooth muscle.","method":"Transgenic mouse enhancer-lacZ reporter assay, electrophoretic mobility shift assay (EMSA), mutagenesis of MEF2 site","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo transgenic reporter with MEF2 site mutagenesis and multiple muscle lineages tested","pmids":["15082771"],"is_preprint":false},{"year":2013,"finding":"Ablation of HRC (knockout mice) results in enhanced SR Ca2+ uptake, enhanced contractility, and elevated SR Ca2+ load, but also increased spontaneous Ca2+ release (sparks, waves) and delayed afterdepolarizations under stress conditions. Under pressure-overload (TAC), HRC-KO mice show severely deteriorated cardiac function, hypertrophy, fibrosis, and decreased survival, associated with depressed SERCA2a expression, indicating HRC is required for maintaining integrity of cardiac Ca2+ cycling under pathophysiological stress.","method":"HRC knockout mouse model, cardiomyocyte Ca2+ imaging, contractility measurements, SR Ca2+ uptake assay, TAC model","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive KO characterization with multiple orthogonal cellular and in vivo readouts","pmids":["23553082"],"is_preprint":false},{"year":2014,"finding":"The human HRC Ser96Ala (S96A) mutation impairs the ability of HRC to buffer intra-store free Ca2+ and inhibit store overload-induced Ca2+ release (SOICR) via RyR2. Wild-type HRC significantly inhibits SOICR by buffering store Ca2+ and inhibiting Ca2+ uptake; the S96A mutant has a markedly suppressed inhibitory effect. A proximity ligation assay showed the S96A mutation also disrupts the Ca2+ microdomain around RyR2 by altering the Ca2+-dependent association of RyR2 and HRC. These effects occur independently of triadin.","method":"HEK293 cell expression of RyR2, cytosolic and intra-store Ca2+ measurements, proximity ligation assay, mutagenesis","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — functional Ca2+ measurements with mutant vs WT, proximity ligation assay for RyR2 interaction, multiple orthogonal methods in one study","pmids":["24805197"],"is_preprint":false},{"year":2015,"finding":"Ablation of HRC in CASQ2 knockout mice (double knockout) alleviates catecholamine-dependent arrhythmia and reduces spontaneous Ca2+ waves and sparks compared to CASQ2-KO alone, and slows SR Ca2+ release restitution. This epistasis demonstrates that CASQ2 and HRC modulate cardiac RyR2-mediated Ca2+ release in opposing manners: CASQ2 stabilizes RyR2 (rendering it refractory), while HRC enhances RyR2 activity and facilitates recovery from refractoriness.","method":"Double knockout mouse model, Ca2+ imaging, arrhythmia measurement under isoproterenol challenge","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in double-KO mouse with multiple cellular Ca2+ readouts and in vivo arrhythmia assessment","pmids":["26410369"],"is_preprint":false},{"year":2015,"finding":"HRC promotes hepatocellular carcinoma cell invasion and migration through Ca2+/CaM signaling-mediated FAK phosphorylation and focal adhesion turnover. Mechanistically, HRC increases cytosolic Ca2+ by inhibiting SERCA2 expression. Knockdown of HRC suppresses invasion/migration, while ectopic expression enhances metastasis in vivo. SATB1 was identified as an upstream transcriptional activator of HRC via AP-1 (JNK-dependent).","method":"siRNA knockdown, ectopic overexpression, in vitro invasion/migration assays, in vivo metastasis model, Ca2+ measurement, FAK phosphorylation western blot, SATB1 reporter assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cellular and in vivo methods, single lab","pmids":["25762622"],"is_preprint":false},{"year":2017,"finding":"Knockdown of HRC in hepatic stellate cells (HSCs) inhibits HSC activation (reduced α-SMA, CTGF, collagen expression, proliferation, migration) through suppression of ER stress and autophagy. TGF-β-induced HSC activation is associated with increased HRC expression. The anti-fibrotic effect of HRC knockdown is mediated via the ER stress pathway.","method":"siRNA knockdown in HSC lines, TGF-β stimulation, western blot for activation/ER stress markers, proliferation and migration assays","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with defined cellular phenotype and pathway placement via ER stress markers, single lab","pmids":["27881436"],"is_preprint":false},{"year":2017,"finding":"The homologous HRC Ser81Ala knock-in mouse (equivalent to human Ser96Ala) exhibits stress-induced ventricular arrhythmias, increased SR Ca2+ leak without increased Ca2+ spark frequency, slower Ca2+ wave propagation, prolonged action potential duration, and increased CaMKII phosphorylation of RyR2. CaMKII inhibitor KN-93 reduced arrhythmia occurrence, placing CaMKII downstream of the HRC Ser96Ala variant in the arrhythmia mechanism.","method":"Knock-in mouse model, Ca2+ imaging, electrophysiology, CaMKII inhibitor treatment, western blot for phospho-RyR2","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with multiple orthogonal electrophysiological and Ca2+ handling readouts, pathway placement via CaMKII inhibitor","pmids":["28859293"],"is_preprint":false},{"year":2012,"finding":"siRNA-mediated HRC knockdown in neonatal cardiomyocytes enhances Ca2+ cycling and increases RyR2 and SERCA2 activities without changing SR Ca2+ load. However, AAV-mediated HRC knockdown in pressure-overloaded (TAC) failing hearts exacerbates cardiac dysfunction and fibrosis, associated with increased phospho-RyR2, phospho-CaMKII, phospho-p38 MAPK, phospho-PLB, and caspase-3 cleavage, indicating that HRC loss in a stressed heart activates CaMKII/p38 MAPK death pathway.","method":"siRNA knockdown in NRVCs, AAV9-mediated knockdown in TAC mouse model, Ca2+ imaging, western blot, TUNEL assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with multiple orthogonal molecular and functional readouts in one study","pmids":["22952658"],"is_preprint":false},{"year":2020,"finding":"Vitamin D reduces HRC expression in liver fibrosis (in vivo CCl4 model and in vitro TGF-β1-stimulated LX-2 cells). HRC overexpression increases TGF-β1/Smad3 signaling and S-phase cell cycle entry. HRC was identified as a direct transcriptional target of the vitamin D receptor (VDR) by chromatin immunoprecipitation (ChIP). Vitamin D reverses HRC-induced TGF-β/Smad signaling.","method":"ChIP assay for VDR at HRC locus, western blot for TGF-β1/Smad3, cell cycle analysis, in vivo CCl4 fibrosis model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes VDR-HRC direct transcriptional regulation, supported by in vitro and in vivo experiments, single lab","pmids":["33309619"],"is_preprint":false},{"year":2021,"finding":"HRC promotes anoikis resistance in hepatocellular carcinoma cells via suppression of ER stress. Modulating HRC level changes ER stress to affect anoikis resistance through the PERK-eIF2α-ATF4-CHOP signaling axis. HRC overexpression also promoted in vivo metastasis.","method":"HRC knockdown/overexpression, suspension culture anoikis assay, western blot for PERK/eIF2α/ATF4/CHOP, in vivo metastasis model","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway placement via known ER stress components with KD/OE and multiple readouts, single lab","pmids":["34400882"],"is_preprint":false},{"year":2022,"finding":"HRC overexpression in hepatocytes induces pyroptosis and HMGB1 release, leading to hepatic stellate cell activation via the NLRP3/caspase-1 pathway. NLRP3 inhibitor MCC950 and caspase-1 inhibitor VX-765 alleviated HRC-mediated pyroptosis and HSC activation.","method":"HRC overexpression in hepatocytes, pyroptosis assays, HMGB1 measurement, pharmacological inhibition of NLRP3 (MCC950) and caspase-1 (VX-765), HSC activation markers","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway placement via pharmacological inhibitors with cellular readouts, single lab","pmids":["36371595"],"is_preprint":false}],"current_model":"HRC (histidine-rich Ca2+-binding protein) is a high-capacity, low-affinity Ca2+-buffering protein residing as a multimer in the SR lumen, where it directly binds triadin (via its histidine-rich acidic repeats in a Ca2+-sensitive manner) and interacts with RyR2 to regulate store-overload-induced Ca2+ release; its transcription is directly driven by MEF2 in all three muscle lineages; it opposes CASQ2 by enhancing RyR2 recovery from refractoriness, and the arrhythmogenic Ser96Ala variant impairs intra-store Ca2+ buffering and disrupts the RyR2 Ca2+ microdomain in a CaMKII-dependent manner; in non-cardiac contexts HRC promotes cell invasion/migration via Ca2+/CaM-FAK signaling and modulates ER stress pathways in hepatic stellate cells and hepatocytes."},"narrative":{"mechanistic_narrative":"HRC (histidine-rich Ca2+-binding protein) is a sarcoplasmic reticulum (SR) luminal Ca2+-buffering protein central to the regulation of cardiac and muscle Ca2+ cycling [PMID:12480542, PMID:23553082]. It resides as a multimeric complex in the SR lumen that dissociates into smaller oligomers as luminal Ca2+ rises, providing a Ca2+-responsive buffering reservoir [PMID:10512736]. Through its histidine-rich acidic repeats, HRC binds the SR membrane protein triadin in a Ca2+-sensitive manner and additionally associates with the ryanodine receptor RyR2, with overexpression elevating SR Ca2+ storage capacity without altering RyR2 density [PMID:11504710, PMID:12480542]. Genetic ablation shows HRC is required to maintain Ca2+-cycling integrity under stress: knockout hearts develop elevated SR load but spontaneous Ca2+ release, delayed afterdepolarizations, and severe decompensation under pressure overload [PMID:23553082, PMID:22952658]. HRC and CASQ2 act in opposing directions on RyR2, HRC enhancing recovery from refractoriness while CASQ2 stabilizes the channel [PMID:26410369]. The arrhythmogenic Ser96Ala variant impairs intra-store Ca2+ buffering, fails to inhibit store-overload-induced Ca2+ release, and disrupts the RyR2 Ca2+ microdomain, producing stress-induced ventricular arrhythmias through CaMKII-dependent RyR2 phosphorylation [PMID:24805197, PMID:28859293]. Its expression in cardiac, skeletal, and arterial smooth muscle is directly driven by MEF2 [PMID:15082771]. In non-muscle contexts, HRC promotes hepatocellular carcinoma invasion and metastasis via Ca2+/CaM-mediated FAK signaling and modulates ER stress pathways governing hepatic stellate cell activation and hepatocyte cell death [PMID:25762622, PMID:27881436, PMID:34400882].","teleology":[{"year":1999,"claim":"Established where HRC sits and how it behaves physically, answering whether it is a membrane or luminal protein and whether its oligomeric state responds to Ca2+.","evidence":"Native gel electrophoresis, tryptic digestion, and biotinylation of SR vesicles","pmids":["10512736"],"confidence":"Medium","gaps":["Functional consequence of the Ca2+-dependent multimer-to-dimer transition not tested in cells","Structural basis of oligomerization unresolved"]},{"year":2001,"claim":"Identified a direct, Ca2+-sensitive molecular partner for HRC, placing it physically within the SR junctional complex via triadin.","evidence":"Co-immunoprecipitation and fusion-protein binding assay with domain mapping in SR","pmids":["11504710"],"confidence":"High","gaps":["Functional role of the HRC-triadin interaction in Ca2+ release not yet tested","Whether RyR2 is part of the same complex not addressed"]},{"year":2003,"claim":"Demonstrated HRC's primary cellular function as an SR Ca2+ buffer, distinguishing buffering from direct channel modulation.","evidence":"Overexpression in neonatal cardiomyocytes with Ca2+ imaging and ryanodine binding","pmids":["12480542"],"confidence":"Medium","gaps":["Loss-of-function consequences not examined","Effect on RyR2 gating beyond receptor density untested"]},{"year":2004,"claim":"Defined the transcriptional control of HRC, establishing MEF2 as the direct, CArG-independent driver of its expression across all three muscle lineages.","evidence":"Transgenic enhancer-lacZ reporter, EMSA, and MEF2-site mutagenesis in mice","pmids":["15082771"],"confidence":"High","gaps":["Upstream signals controlling MEF2-driven HRC expression not defined","Regulation outside muscle not addressed"]},{"year":2012,"claim":"Showed that HRC loss has opposite consequences in healthy versus stressed hearts, revealing a protective role against CaMKII/p38-driven death signaling under pressure overload.","evidence":"siRNA knockdown in NRVCs and AAV9 knockdown in TAC mice with Ca2+ imaging, western blot, TUNEL","pmids":["22952658"],"confidence":"High","gaps":["Direct link between HRC buffering and CaMKII/p38 activation not mechanistically resolved","Whether changes are cell-autonomous unclear"]},{"year":2013,"claim":"Comprehensive knockout established HRC as required for Ca2+-cycling integrity and survival under pathophysiological stress despite enhanced baseline contractility.","evidence":"HRC knockout mice with cardiomyocyte Ca2+ imaging, contractility, SR uptake, and TAC","pmids":["23553082"],"confidence":"High","gaps":["Mechanism linking HRC loss to depressed SERCA2a expression unresolved","Relationship between elevated SR load and arrhythmogenic release not fully reconciled"]},{"year":2014,"claim":"Defined the molecular defect of the arrhythmogenic Ser96Ala variant: impaired intra-store buffering and disruption of the RyR2 Ca2+ microdomain, independent of triadin.","evidence":"HEK293 RyR2 reconstitution, intra-store Ca2+ measurement, proximity ligation assay, mutagenesis","pmids":["24805197"],"confidence":"High","gaps":["Heterologous system lacks native junctional partners","How a single residue alters Ca2+-dependent RyR2 association structurally unknown"]},{"year":2015,"claim":"Genetic epistasis placed HRC and CASQ2 as opposing regulators of RyR2 refractoriness, clarifying how HRC enhances recovery and facilitates Ca2+ release.","evidence":"CASQ2/HRC double-knockout mice with Ca2+ imaging and isoproterenol arrhythmia assay","pmids":["26410369"],"confidence":"High","gaps":["Molecular basis of the opposing actions on RyR2 not defined","Whether HRC and CASQ2 compete for the same RyR2 site unknown"]},{"year":2017,"claim":"Knock-in of the variant in vivo confirmed CaMKII as the downstream effector of Ser96Ala arrhythmogenesis, linking impaired buffering to RyR2 hyperphosphorylation and SR leak.","evidence":"Ser81Ala knock-in mouse with Ca2+ imaging, electrophysiology, KN-93, phospho-RyR2 western blot","pmids":["28859293"],"confidence":"High","gaps":["How impaired buffering activates CaMKII mechanistically not resolved","Whether human carriers show identical pathway dependence untested"]},{"year":2017,"claim":"Extended HRC function beyond muscle, implicating it in hepatic stellate cell activation through ER stress and autophagy.","evidence":"siRNA knockdown in HSC lines with TGF-β stimulation and activation/ER-stress marker western blots","pmids":["27881436"],"confidence":"Medium","gaps":["Direct molecular target of HRC in ER stress not identified","Whether luminal Ca2+ buffering underlies the effect untested"]},{"year":2015,"claim":"Established a pro-metastatic role for HRC in hepatocellular carcinoma via cytosolic Ca2+/CaM-FAK signaling and identified its upstream transcriptional activator SATB1.","evidence":"Knockdown/overexpression, invasion/migration and in vivo metastasis assays, FAK phospho-western, SATB1 reporter","pmids":["25762622"],"confidence":"Medium","gaps":["Mechanism by which HRC suppresses SERCA2 expression unknown","Single lab; CaM-FAK axis not independently confirmed"]},{"year":2020,"claim":"Identified VDR as a direct transcriptional regulator of HRC in liver fibrosis, connecting vitamin D signaling to HRC-driven TGF-β/Smad activation.","evidence":"ChIP for VDR at the HRC locus, TGF-β1/Smad3 western blots, cell cycle analysis, CCl4 fibrosis model","pmids":["33309619"],"confidence":"Medium","gaps":["How HRC amplifies TGF-β/Smad signaling mechanistically unresolved","Single lab"]},{"year":2021,"claim":"Linked HRC to anoikis resistance in hepatocellular carcinoma through suppression of the PERK-eIF2α-ATF4-CHOP ER stress axis.","evidence":"Knockdown/overexpression, suspension anoikis assay, ER-stress pathway western blots, in vivo metastasis","pmids":["34400882"],"confidence":"Medium","gaps":["Direct interaction between HRC and ER stress sensors not shown","Single lab"]},{"year":2022,"claim":"Showed HRC overexpression in hepatocytes drives pyroptosis and HMGB1 release that activates hepatic stellate cells via NLRP3/caspase-1.","evidence":"Hepatocyte overexpression, pyroptosis and HMGB1 assays, MCC950 and VX-765 inhibition, HSC markers","pmids":["36371595"],"confidence":"Medium","gaps":["Connection between HRC's Ca2+-buffering role and NLRP3 activation unclear","Single lab"]},{"year":null,"claim":"How HRC's defined luminal Ca2+-buffering biochemistry mechanistically translates into its diverse non-muscle effects on ER stress, TGF-β/Smad signaling, and inflammasome activation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying molecular mechanism linking SR/ER Ca2+ buffering to hepatic ER stress and cell death pathways","Structure of HRC and its Ca2+-dependent conformational changes undetermined","Mechanism by which HRC suppresses SERCA2 expression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,0]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,11]}],"complexes":[],"partners":["TRDN","RYR2","SERCA2","CASQ2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23327","full_name":"Sarcoplasmic reticulum histidine-rich calcium-binding protein","aliases":[],"length_aa":699,"mass_kda":80.2,"function":"May play a role in the regulation of calcium sequestration or release in the SR of skeletal and cardiac muscle","subcellular_location":"Sarcoplasmic reticulum lumen","url":"https://www.uniprot.org/uniprotkb/P23327/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HRC","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HRC","total_profiled":1310},"omim":[{"mim_id":"619773","title":"IMMUNODEFICIENCY 95; IMD95","url":"https://www.omim.org/entry/619773"},{"mim_id":"607585","title":"ATM SERINE/THREONINE KINASE; ATM","url":"https://www.omim.org/entry/607585"},{"mim_id":"606951","title":"INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; IFIH1","url":"https://www.omim.org/entry/606951"},{"mim_id":"606159","title":"NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3; NBIA3","url":"https://www.omim.org/entry/606159"},{"mim_id":"605041","title":"BROOKE-SPIEGLER SYNDROME; BRSS","url":"https://www.omim.org/entry/605041"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":692.1},{"tissue":"skeletal muscle","ntpm":424.2},{"tissue":"tongue","ntpm":228.2}],"url":"https://www.proteinatlas.org/search/HRC"},"hgnc":{"alias_symbol":["MGC133236"],"prev_symbol":[]},"alphafold":{"accession":"P23327","domains":[{"cath_id":"-","chopping":"626-695","consensus_level":"medium","plddt":83.8279,"start":626,"end":695}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23327","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23327-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23327-F1-predicted_aligned_error_v6.png","plddt_mean":50.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HRC","jax_strain_url":"https://www.jax.org/strain/search?query=HRC"},"sequence":{"accession":"P23327","fasta_url":"https://rest.uniprot.org/uniprotkb/P23327.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23327/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23327"}},"corpus_meta":[{"pmid":"20455697","id":"PMC_20455697","title":"Playing the 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The histidine-rich acidic repeats of HRC were identified as responsible for this binding via fusion protein binding assay. The HRC-binding domain of triadin was localized to the lumenal region containing the KEKE motif. Importantly, the interaction is Ca2+-sensitive.\",\n      \"method\": \"Co-immunoprecipitation and fusion protein binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with domain mapping, single lab but two orthogonal methods\",\n      \"pmids\": [\"11504710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HRC exists as a multimeric complex (likely larger than a pentamer) under physiological conditions in the SR lumen; at higher Ca2+ concentrations the complex dissociates into dimers or trimers. HRC resides in the lumen of the SR (not the membrane), confirmed by tryptic digestion and biotinylation of SR vesicles.\",\n      \"method\": \"Native gel electrophoresis, tryptic digestion of SR vesicles, biotinylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods in one study, single lab\",\n      \"pmids\": [\"10512736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of HRC in rat neonatal cardiomyocytes increases SR Ca2+ storage capacity: caffeine-induced and depolarization-induced Ca2+ release were significantly increased, and SR Ca2+ content (measured by cyclopiazonic acid depletion) remained elevated. Ryanodine receptor density and binding kinetics were not significantly altered, implicating HRC primarily in SR Ca2+ buffering.\",\n      \"method\": \"Overexpression in neonatal cardiomyocytes, Ca2+ imaging, ryanodine binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular assay with multiple Ca2+ readouts, single lab\",\n      \"pmids\": [\"12480542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HRC gene expression in cardiac, skeletal, and arterial smooth muscle is directly controlled by MEF2 transcription factor. A conserved MEF2 binding site in the HRC enhancer was shown to be required for expression in all three muscle lineages in transgenic mice. The HRC enhancer lacks CArG motifs and is not activated by SRF, making HRC the first MEF2-dependent, CArG-independent SR gene transcriptional target in smooth muscle.\",\n      \"method\": \"Transgenic mouse enhancer-lacZ reporter assay, electrophoretic mobility shift assay (EMSA), mutagenesis of MEF2 site\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo transgenic reporter with MEF2 site mutagenesis and multiple muscle lineages tested\",\n      \"pmids\": [\"15082771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ablation of HRC (knockout mice) results in enhanced SR Ca2+ uptake, enhanced contractility, and elevated SR Ca2+ load, but also increased spontaneous Ca2+ release (sparks, waves) and delayed afterdepolarizations under stress conditions. Under pressure-overload (TAC), HRC-KO mice show severely deteriorated cardiac function, hypertrophy, fibrosis, and decreased survival, associated with depressed SERCA2a expression, indicating HRC is required for maintaining integrity of cardiac Ca2+ cycling under pathophysiological stress.\",\n      \"method\": \"HRC knockout mouse model, cardiomyocyte Ca2+ imaging, contractility measurements, SR Ca2+ uptake assay, TAC model\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive KO characterization with multiple orthogonal cellular and in vivo readouts\",\n      \"pmids\": [\"23553082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The human HRC Ser96Ala (S96A) mutation impairs the ability of HRC to buffer intra-store free Ca2+ and inhibit store overload-induced Ca2+ release (SOICR) via RyR2. Wild-type HRC significantly inhibits SOICR by buffering store Ca2+ and inhibiting Ca2+ uptake; the S96A mutant has a markedly suppressed inhibitory effect. A proximity ligation assay showed the S96A mutation also disrupts the Ca2+ microdomain around RyR2 by altering the Ca2+-dependent association of RyR2 and HRC. These effects occur independently of triadin.\",\n      \"method\": \"HEK293 cell expression of RyR2, cytosolic and intra-store Ca2+ measurements, proximity ligation assay, mutagenesis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional Ca2+ measurements with mutant vs WT, proximity ligation assay for RyR2 interaction, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24805197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ablation of HRC in CASQ2 knockout mice (double knockout) alleviates catecholamine-dependent arrhythmia and reduces spontaneous Ca2+ waves and sparks compared to CASQ2-KO alone, and slows SR Ca2+ release restitution. This epistasis demonstrates that CASQ2 and HRC modulate cardiac RyR2-mediated Ca2+ release in opposing manners: CASQ2 stabilizes RyR2 (rendering it refractory), while HRC enhances RyR2 activity and facilitates recovery from refractoriness.\",\n      \"method\": \"Double knockout mouse model, Ca2+ imaging, arrhythmia measurement under isoproterenol challenge\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in double-KO mouse with multiple cellular Ca2+ readouts and in vivo arrhythmia assessment\",\n      \"pmids\": [\"26410369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HRC promotes hepatocellular carcinoma cell invasion and migration through Ca2+/CaM signaling-mediated FAK phosphorylation and focal adhesion turnover. Mechanistically, HRC increases cytosolic Ca2+ by inhibiting SERCA2 expression. Knockdown of HRC suppresses invasion/migration, while ectopic expression enhances metastasis in vivo. SATB1 was identified as an upstream transcriptional activator of HRC via AP-1 (JNK-dependent).\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, in vitro invasion/migration assays, in vivo metastasis model, Ca2+ measurement, FAK phosphorylation western blot, SATB1 reporter assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cellular and in vivo methods, single lab\",\n      \"pmids\": [\"25762622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of HRC in hepatic stellate cells (HSCs) inhibits HSC activation (reduced α-SMA, CTGF, collagen expression, proliferation, migration) through suppression of ER stress and autophagy. TGF-β-induced HSC activation is associated with increased HRC expression. The anti-fibrotic effect of HRC knockdown is mediated via the ER stress pathway.\",\n      \"method\": \"siRNA knockdown in HSC lines, TGF-β stimulation, western blot for activation/ER stress markers, proliferation and migration assays\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with defined cellular phenotype and pathway placement via ER stress markers, single lab\",\n      \"pmids\": [\"27881436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The homologous HRC Ser81Ala knock-in mouse (equivalent to human Ser96Ala) exhibits stress-induced ventricular arrhythmias, increased SR Ca2+ leak without increased Ca2+ spark frequency, slower Ca2+ wave propagation, prolonged action potential duration, and increased CaMKII phosphorylation of RyR2. CaMKII inhibitor KN-93 reduced arrhythmia occurrence, placing CaMKII downstream of the HRC Ser96Ala variant in the arrhythmia mechanism.\",\n      \"method\": \"Knock-in mouse model, Ca2+ imaging, electrophysiology, CaMKII inhibitor treatment, western blot for phospho-RyR2\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with multiple orthogonal electrophysiological and Ca2+ handling readouts, pathway placement via CaMKII inhibitor\",\n      \"pmids\": [\"28859293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"siRNA-mediated HRC knockdown in neonatal cardiomyocytes enhances Ca2+ cycling and increases RyR2 and SERCA2 activities without changing SR Ca2+ load. However, AAV-mediated HRC knockdown in pressure-overloaded (TAC) failing hearts exacerbates cardiac dysfunction and fibrosis, associated with increased phospho-RyR2, phospho-CaMKII, phospho-p38 MAPK, phospho-PLB, and caspase-3 cleavage, indicating that HRC loss in a stressed heart activates CaMKII/p38 MAPK death pathway.\",\n      \"method\": \"siRNA knockdown in NRVCs, AAV9-mediated knockdown in TAC mouse model, Ca2+ imaging, western blot, TUNEL assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with multiple orthogonal molecular and functional readouts in one study\",\n      \"pmids\": [\"22952658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Vitamin D reduces HRC expression in liver fibrosis (in vivo CCl4 model and in vitro TGF-β1-stimulated LX-2 cells). HRC overexpression increases TGF-β1/Smad3 signaling and S-phase cell cycle entry. HRC was identified as a direct transcriptional target of the vitamin D receptor (VDR) by chromatin immunoprecipitation (ChIP). Vitamin D reverses HRC-induced TGF-β/Smad signaling.\",\n      \"method\": \"ChIP assay for VDR at HRC locus, western blot for TGF-β1/Smad3, cell cycle analysis, in vivo CCl4 fibrosis model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes VDR-HRC direct transcriptional regulation, supported by in vitro and in vivo experiments, single lab\",\n      \"pmids\": [\"33309619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HRC promotes anoikis resistance in hepatocellular carcinoma cells via suppression of ER stress. Modulating HRC level changes ER stress to affect anoikis resistance through the PERK-eIF2α-ATF4-CHOP signaling axis. HRC overexpression also promoted in vivo metastasis.\",\n      \"method\": \"HRC knockdown/overexpression, suspension culture anoikis assay, western blot for PERK/eIF2α/ATF4/CHOP, in vivo metastasis model\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway placement via known ER stress components with KD/OE and multiple readouts, single lab\",\n      \"pmids\": [\"34400882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HRC overexpression in hepatocytes induces pyroptosis and HMGB1 release, leading to hepatic stellate cell activation via the NLRP3/caspase-1 pathway. NLRP3 inhibitor MCC950 and caspase-1 inhibitor VX-765 alleviated HRC-mediated pyroptosis and HSC activation.\",\n      \"method\": \"HRC overexpression in hepatocytes, pyroptosis assays, HMGB1 measurement, pharmacological inhibition of NLRP3 (MCC950) and caspase-1 (VX-765), HSC activation markers\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway placement via pharmacological inhibitors with cellular readouts, single lab\",\n      \"pmids\": [\"36371595\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HRC (histidine-rich Ca2+-binding protein) is a high-capacity, low-affinity Ca2+-buffering protein residing as a multimer in the SR lumen, where it directly binds triadin (via its histidine-rich acidic repeats in a Ca2+-sensitive manner) and interacts with RyR2 to regulate store-overload-induced Ca2+ release; its transcription is directly driven by MEF2 in all three muscle lineages; it opposes CASQ2 by enhancing RyR2 recovery from refractoriness, and the arrhythmogenic Ser96Ala variant impairs intra-store Ca2+ buffering and disrupts the RyR2 Ca2+ microdomain in a CaMKII-dependent manner; in non-cardiac contexts HRC promotes cell invasion/migration via Ca2+/CaM-FAK signaling and modulates ER stress pathways in hepatic stellate cells and hepatocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HRC (histidine-rich Ca2+-binding protein) is a sarcoplasmic reticulum (SR) luminal Ca2+-buffering protein central to the regulation of cardiac and muscle Ca2+ cycling [#2, #4]. It resides as a multimeric complex in the SR lumen that dissociates into smaller oligomers as luminal Ca2+ rises, providing a Ca2+-responsive buffering reservoir [#1]. Through its histidine-rich acidic repeats, HRC binds the SR membrane protein triadin in a Ca2+-sensitive manner and additionally associates with the ryanodine receptor RyR2, with overexpression elevating SR Ca2+ storage capacity without altering RyR2 density [#0, #2]. Genetic ablation shows HRC is required to maintain Ca2+-cycling integrity under stress: knockout hearts develop elevated SR load but spontaneous Ca2+ release, delayed afterdepolarizations, and severe decompensation under pressure overload [#4, #10]. HRC and CASQ2 act in opposing directions on RyR2, HRC enhancing recovery from refractoriness while CASQ2 stabilizes the channel [#6]. The arrhythmogenic Ser96Ala variant impairs intra-store Ca2+ buffering, fails to inhibit store-overload-induced Ca2+ release, and disrupts the RyR2 Ca2+ microdomain, producing stress-induced ventricular arrhythmias through CaMKII-dependent RyR2 phosphorylation [#5, #9]. Its expression in cardiac, skeletal, and arterial smooth muscle is directly driven by MEF2 [#3]. In non-muscle contexts, HRC promotes hepatocellular carcinoma invasion and metastasis via Ca2+/CaM-mediated FAK signaling and modulates ER stress pathways governing hepatic stellate cell activation and hepatocyte cell death [#7, #8, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established where HRC sits and how it behaves physically, answering whether it is a membrane or luminal protein and whether its oligomeric state responds to Ca2+.\",\n      \"evidence\": \"Native gel electrophoresis, tryptic digestion, and biotinylation of SR vesicles\",\n      \"pmids\": [\"10512736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the Ca2+-dependent multimer-to-dimer transition not tested in cells\", \"Structural basis of oligomerization unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified a direct, Ca2+-sensitive molecular partner for HRC, placing it physically within the SR junctional complex via triadin.\",\n      \"evidence\": \"Co-immunoprecipitation and fusion-protein binding assay with domain mapping in SR\",\n      \"pmids\": [\"11504710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the HRC-triadin interaction in Ca2+ release not yet tested\", \"Whether RyR2 is part of the same complex not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated HRC's primary cellular function as an SR Ca2+ buffer, distinguishing buffering from direct channel modulation.\",\n      \"evidence\": \"Overexpression in neonatal cardiomyocytes with Ca2+ imaging and ryanodine binding\",\n      \"pmids\": [\"12480542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loss-of-function consequences not examined\", \"Effect on RyR2 gating beyond receptor density untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the transcriptional control of HRC, establishing MEF2 as the direct, CArG-independent driver of its expression across all three muscle lineages.\",\n      \"evidence\": \"Transgenic enhancer-lacZ reporter, EMSA, and MEF2-site mutagenesis in mice\",\n      \"pmids\": [\"15082771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling MEF2-driven HRC expression not defined\", \"Regulation outside muscle not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that HRC loss has opposite consequences in healthy versus stressed hearts, revealing a protective role against CaMKII/p38-driven death signaling under pressure overload.\",\n      \"evidence\": \"siRNA knockdown in NRVCs and AAV9 knockdown in TAC mice with Ca2+ imaging, western blot, TUNEL\",\n      \"pmids\": [\"22952658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between HRC buffering and CaMKII/p38 activation not mechanistically resolved\", \"Whether changes are cell-autonomous unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Comprehensive knockout established HRC as required for Ca2+-cycling integrity and survival under pathophysiological stress despite enhanced baseline contractility.\",\n      \"evidence\": \"HRC knockout mice with cardiomyocyte Ca2+ imaging, contractility, SR uptake, and TAC\",\n      \"pmids\": [\"23553082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking HRC loss to depressed SERCA2a expression unresolved\", \"Relationship between elevated SR load and arrhythmogenic release not fully reconciled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the molecular defect of the arrhythmogenic Ser96Ala variant: impaired intra-store buffering and disruption of the RyR2 Ca2+ microdomain, independent of triadin.\",\n      \"evidence\": \"HEK293 RyR2 reconstitution, intra-store Ca2+ measurement, proximity ligation assay, mutagenesis\",\n      \"pmids\": [\"24805197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterologous system lacks native junctional partners\", \"How a single residue alters Ca2+-dependent RyR2 association structurally unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic epistasis placed HRC and CASQ2 as opposing regulators of RyR2 refractoriness, clarifying how HRC enhances recovery and facilitates Ca2+ release.\",\n      \"evidence\": \"CASQ2/HRC double-knockout mice with Ca2+ imaging and isoproterenol arrhythmia assay\",\n      \"pmids\": [\"26410369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the opposing actions on RyR2 not defined\", \"Whether HRC and CASQ2 compete for the same RyR2 site unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Knock-in of the variant in vivo confirmed CaMKII as the downstream effector of Ser96Ala arrhythmogenesis, linking impaired buffering to RyR2 hyperphosphorylation and SR leak.\",\n      \"evidence\": \"Ser81Ala knock-in mouse with Ca2+ imaging, electrophysiology, KN-93, phospho-RyR2 western blot\",\n      \"pmids\": [\"28859293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How impaired buffering activates CaMKII mechanistically not resolved\", \"Whether human carriers show identical pathway dependence untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended HRC function beyond muscle, implicating it in hepatic stellate cell activation through ER stress and autophagy.\",\n      \"evidence\": \"siRNA knockdown in HSC lines with TGF-\\u03b2 stimulation and activation/ER-stress marker western blots\",\n      \"pmids\": [\"27881436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of HRC in ER stress not identified\", \"Whether luminal Ca2+ buffering underlies the effect untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a pro-metastatic role for HRC in hepatocellular carcinoma via cytosolic Ca2+/CaM-FAK signaling and identified its upstream transcriptional activator SATB1.\",\n      \"evidence\": \"Knockdown/overexpression, invasion/migration and in vivo metastasis assays, FAK phospho-western, SATB1 reporter\",\n      \"pmids\": [\"25762622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HRC suppresses SERCA2 expression unknown\", \"Single lab; CaM-FAK axis not independently confirmed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified VDR as a direct transcriptional regulator of HRC in liver fibrosis, connecting vitamin D signaling to HRC-driven TGF-\\u03b2/Smad activation.\",\n      \"evidence\": \"ChIP for VDR at the HRC locus, TGF-\\u03b21/Smad3 western blots, cell cycle analysis, CCl4 fibrosis model\",\n      \"pmids\": [\"33309619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HRC amplifies TGF-\\u03b2/Smad signaling mechanistically unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked HRC to anoikis resistance in hepatocellular carcinoma through suppression of the PERK-eIF2\\u03b1-ATF4-CHOP ER stress axis.\",\n      \"evidence\": \"Knockdown/overexpression, suspension anoikis assay, ER-stress pathway western blots, in vivo metastasis\",\n      \"pmids\": [\"34400882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction between HRC and ER stress sensors not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed HRC overexpression in hepatocytes drives pyroptosis and HMGB1 release that activates hepatic stellate cells via NLRP3/caspase-1.\",\n      \"evidence\": \"Hepatocyte overexpression, pyroptosis and HMGB1 assays, MCC950 and VX-765 inhibition, HSC markers\",\n      \"pmids\": [\"36371595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between HRC's Ca2+-buffering role and NLRP3 activation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HRC's defined luminal Ca2+-buffering biochemistry mechanistically translates into its diverse non-muscle effects on ER stress, TGF-\\u03b2/Smad signaling, and inflammasome activation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying molecular mechanism linking SR/ER Ca2+ buffering to hepatic ER stress and cell death pathways\", \"Structure of HRC and its Ca2+-dependent conformational changes undetermined\", \"Mechanism by which HRC suppresses SERCA2 expression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRDN\", \"RYR2\", \"SERCA2\", \"CASQ2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}