Affinage

HRC

Sarcoplasmic reticulum histidine-rich calcium-binding protein · UniProt P23327

Length
699 aa
Mass
80.2 kDa
Annotated
2026-06-10
33 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 Medium

    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

    PMID:10512736

    Open questions at the time
    • Functional consequence of the Ca2+-dependent multimer-to-dimer transition not tested in cells
    • Structural basis of oligomerization unresolved
  2. 2001 High

    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

    PMID:11504710

    Open questions at the time
    • Functional role of the HRC-triadin interaction in Ca2+ release not yet tested
    • Whether RyR2 is part of the same complex not addressed
  3. 2003 Medium

    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

    PMID:12480542

    Open questions at the time
    • Loss-of-function consequences not examined
    • Effect on RyR2 gating beyond receptor density untested
  4. 2004 High

    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

    PMID:15082771

    Open questions at the time
    • Upstream signals controlling MEF2-driven HRC expression not defined
    • Regulation outside muscle not addressed
  5. 2012 High

    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

    PMID:22952658

    Open questions at the time
    • Direct link between HRC buffering and CaMKII/p38 activation not mechanistically resolved
    • Whether changes are cell-autonomous unclear
  6. 2013 High

    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

    PMID:23553082

    Open questions at the time
    • Mechanism linking HRC loss to depressed SERCA2a expression unresolved
    • Relationship between elevated SR load and arrhythmogenic release not fully reconciled
  7. 2014 High

    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

    PMID:24805197

    Open questions at the time
    • Heterologous system lacks native junctional partners
    • How a single residue alters Ca2+-dependent RyR2 association structurally unknown
  8. 2015 High

    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

    PMID:26410369

    Open questions at the time
    • Molecular basis of the opposing actions on RyR2 not defined
    • Whether HRC and CASQ2 compete for the same RyR2 site unknown
  9. 2017 High

    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

    PMID:28859293

    Open questions at the time
    • How impaired buffering activates CaMKII mechanistically not resolved
    • Whether human carriers show identical pathway dependence untested
  10. 2017 Medium

    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

    PMID:27881436

    Open questions at the time
    • Direct molecular target of HRC in ER stress not identified
    • Whether luminal Ca2+ buffering underlies the effect untested
  11. 2015 Medium

    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

    PMID:25762622

    Open questions at the time
    • Mechanism by which HRC suppresses SERCA2 expression unknown
    • Single lab; CaM-FAK axis not independently confirmed
  12. 2020 Medium

    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

    PMID:33309619

    Open questions at the time
    • How HRC amplifies TGF-β/Smad signaling mechanistically unresolved
    • Single lab
  13. 2021 Medium

    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

    PMID:34400882

    Open questions at the time
    • Direct interaction between HRC and ER stress sensors not shown
    • Single lab
  14. 2022 Medium

    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

    PMID:36371595

    Open questions at the time
    • Connection between HRC's Ca2+-buffering role and NLRP3 activation unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140313 molecular sequestering activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-397014 Muscle contraction 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CASQ2RYR2SERCA2TRDN

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Co-immunoprecipitation and fusion protein binding assay The Journal of biological chemistry High 11504710
1999 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. Native gel electrophoresis, tryptic digestion of SR vesicles, biotinylation assay Biochemical and biophysical research communications Medium 10512736
2003 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. Overexpression in neonatal cardiomyocytes, Ca2+ imaging, ryanodine binding assay Biochemical and biophysical research communications Medium 12480542
2004 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. Transgenic mouse enhancer-lacZ reporter assay, electrophoretic mobility shift assay (EMSA), mutagenesis of MEF2 site Molecular and cellular biology High 15082771
2013 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. HRC knockout mouse model, cardiomyocyte Ca2+ imaging, contractility measurements, SR Ca2+ uptake assay, TAC model Basic research in cardiology High 23553082
2014 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. HEK293 cell expression of RyR2, cytosolic and intra-store Ca2+ measurements, proximity ligation assay, mutagenesis Journal of molecular and cellular cardiology High 24805197
2015 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. Double knockout mouse model, Ca2+ imaging, arrhythmia measurement under isoproterenol challenge Cardiovascular research High 26410369
2015 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). siRNA knockdown, ectopic overexpression, in vitro invasion/migration assays, in vivo metastasis model, Ca2+ measurement, FAK phosphorylation western blot, SATB1 reporter assay Oncotarget Medium 25762622
2017 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. siRNA knockdown in HSC lines, TGF-β stimulation, western blot for activation/ER stress markers, proliferation and migration assays Biology open Medium 27881436
2017 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. Knock-in mouse model, Ca2+ imaging, electrophysiology, CaMKII inhibitor treatment, western blot for phospho-RyR2 Cardiovascular research High 28859293
2012 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. siRNA knockdown in NRVCs, AAV9-mediated knockdown in TAC mouse model, Ca2+ imaging, western blot, TUNEL assay PloS one High 22952658
2020 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. ChIP assay for VDR at HRC locus, western blot for TGF-β1/Smad3, cell cycle analysis, in vivo CCl4 fibrosis model Chemico-biological interactions Medium 33309619
2021 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. HRC knockdown/overexpression, suspension culture anoikis assay, western blot for PERK/eIF2α/ATF4/CHOP, in vivo metastasis model International journal of medical sciences Medium 34400882
2022 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. HRC overexpression in hepatocytes, pyroptosis assays, HMGB1 measurement, pharmacological inhibition of NLRP3 (MCC950) and caspase-1 (VX-765), HSC activation markers Journal of molecular medicine (Berlin, Germany) Medium 36371595

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Playing the "Harp": evolution of our understanding of hrp/hrc genes. Annual review of phytopathology 88 20455697
1994 The putative glioma tumor suppressor gene on chromosome 19q maps between APOC2 and HRC. Cancer research 81 8062276
2020 Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain. mBio 70 33082259
2001 Interaction of HRC (histidine-rich Ca(2+)-binding protein) and triadin in the lumen of sarcoplasmic reticulum. The Journal of biological chemistry 62 11504710
2010 Pseudomonas syringae strains naturally lacking the classical P. syringae hrp/hrc Locus are common leaf colonizers equipped with an atypical type III secretion system. Molecular plant-microbe interactions : MPMI 60 20064063
2014 The post-transcriptional regulator rsmA/csrA activates T3SS by stabilizing the 5' UTR of hrpG, the master regulator of hrp/hrc genes, in Xanthomonas. PLoS pathogens 56 24586158
2004 HRC is a direct transcriptional target of MEF2 during cardiac, skeletal, and arterial smooth muscle development in vivo. Molecular and cellular biology 54 15082771
2003 Mutations in the putative HR-C region of the measles virus F2 glycoprotein modulate syncytium formation. Journal of virology 51 12634376
2011 A novel regulatory role of HrpD6 in regulating hrp-hrc-hpa genes in Xanthomonas oryzae pv. oryzicola. Molecular plant-microbe interactions : MPMI 50 21615204
1991 cDNA and genomic cloning of HRC, a human sarcoplasmic reticulum protein, and localization of the gene to human chromosome 19 and mouse chromosome 7. Genomics 41 2037293
2003 Increased Ca2+ storage capacity in the sarcoplasmic reticulum by overexpression of HRC (histidine-rich Ca2+ binding protein). Biochemical and biophysical research communications 33 12480542
1999 HRC (histidine-rich Ca2+ binding protein) resides in the lumen of sarcoplasmic reticulum as a multimer. Biochemical and biophysical research communications 32 10512736
2013 Targeted ablation of the histidine-rich Ca(2+)-binding protein (HRC) gene is associated with abnormal SR Ca(2+)-cycling and severe pathology under pressure-overload stress. Basic research in cardiology 28 23553082
2019 Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease. PloS one 27 31283791
2015 The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1. Oncotarget 21 25762622
2021 HRC promotes anoikis resistance and metastasis by suppressing endoplasmic reticulum stress in hepatocellular carcinoma. International journal of medical sciences 20 34400882
2020 Vitamin D alleviates liver fibrosis by inhibiting histidine-rich calcium binding protein (HRC). Chemico-biological interactions 20 33309619
2004 The Erwinia chrysanthemi EC16 hrp/hrc gene cluster encodes an active Hrp type III secretion system that is flanked by virulence genes functionally unrelated to the Hrp system. Molecular plant-microbe interactions : MPMI 20 15195947
2015 Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT. Cardiovascular research 19 26410369
2014 The arrhythmogenic human HRC point mutation S96A leads to spontaneous Ca(2+) release due to an impaired ability to buffer store Ca(2+). Journal of molecular and cellular cardiology 19 24805197
2017 Impaired calcium homeostasis is associated with sudden cardiac death and arrhythmias in a genetic equivalent mouse model of the human HRC-Ser96Ala variant. Cardiovascular research 16 28859293
2012 AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure. PloS one 15 22952658
2006 Biophysical characterization of HRC peptide analogs interaction with heptad repeat regions of the SARS-coronavirus Spike fusion protein core. Journal of structural biology 10 16765058
2007 The novel hemoglobin-based oxygen carrier HRC 101 improves survival in murine sickle cell disease. Anesthesiology 9 17667573
2022 Hepatic HRC induces hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway. Journal of molecular medicine (Berlin, Germany) 7 36371595
2022 Apoptotic-like PCD inducing HRC gene when silenced enhances multiple disease resistance in plants. Scientific reports 6 36437285
2017 Knockdown of histidine-rich calcium-binding protein (HRC) suppresses liver fibrosis by inhibiting the activation of hepatic stellate cells. Biology open 6 27881436
2006 In vitro and in vivo evaluation of LEUKOSEP HRC-600-C leukoreduction filtration system for red cells. Transfusion 6 16934065
2015 Effect of antisense microRNA targeting survivin on rectal cancer HRC-9698 cells and its mechanism. International journal of clinical and experimental pathology 4 26261483
2023 Non‑synonymous polymorphisms in the HRC and ADRB1 genes may be associated with all‑cause death in patients with non‑ischemic heart failure. Experimental and therapeutic medicine 2 38144921
2006 Construction of a bacterial artificial chromosome library and characterization of hrp/hrc gene cluster of Pseudomonas syringae pathovar tagetis LMG5090. Biotechnology letters 2 16799767
2026 Design and Characterization of an HRC-Derived Peptide Inhibitor of Canine Coronavirus Spike-Mediated Fusion. Pathogens (Basel, Switzerland) 0 41901768
2026 A self-assembled nanoparticle vaccine displaying chimeric and trimeric RBD-HRC elicits broad-spectrum neutralizing antibodies against multiple coronaviruses. Microbiology spectrum 0 41910140

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