Affinage

HSPA5

Endoplasmic reticulum chaperone BiP · UniProt P11021

Length
654 aa
Mass
72.3 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPA5 (BiP/GRP78) is the principal ER-luminal HSP70-family chaperone that couples protein folding capacity to cellular stress responses (PMID:10597629, PMID:15804610). It is an ATP-driven machine that binds nascent and unfolded secretory proteins, maintaining them in a folding-competent state during ER translocation and triaging aberrant proteins to ERAD (PMID:10597629); its intrinsic ATPase activity drives conformational cycling between protease-resistant ADP-bound and ATP-bound states (PMID:1325440), and this cycle is stimulated by DnaJ-type co-chaperones such as the transmembrane protein MTJ1 (PMID:10777498), with GRP94 acting upstream to hand off misfolded clients to the BiP system (PMID:35905823). ATPase-competent HSPA5 is required for folding and maturation of specific clients including APP (PMID:9748217), and inadequate BiP availability relative to unfolded substrate is the defining molecular trigger of proteotoxic ER stress (PMID:30869076). Centrally, HSPA5 governs the unfolded protein response by binding and sequestering the three transmembrane sensors IRE1, PERK, and ATF6 in their inactive states until accumulating unfolded protein titrates it away, releasing the sensors and coupling folding capacity to ATF6, PERK, and IRE1 activation (PMID:12110159, PMID:15804610). HSPA5 abundance and activity are tuned by an extensive post-translational regulatory network: AMPylation at Thr518/Thr366 by HYPE/FicD modulates its ATPase activity (PMID:33942205); ubiquitination at K447/K446 by GP78, MUL1, and NLRP6-promoted pathways drives proteasomal degradation (PMID:26119938, PMID:29260979, PMID:32682010), opposed by the deubiquitylase OTUD3 (PMID:31266968); acetylation at K353 by EP300 and at K633, controlled by HDAC6, regulates ferroptosis sensitivity and exosomal secretion (PMID:26119938, PMID:27460191, PMID:37696842); and palmitoylation at Cys420 by ZDHHC9 stabilizes the protein and its ER localization (PMID:39002690). Beyond the ER, HSPA5 acquires distinct functions through relocalization: cytosolic N-terminal arginylation by ATE1 generates R-HSPA5, which engages the SQSTM1/p62 ZZ domain to direct misfolded cargoes—and ubiquitinated AKT—to selective autophagy (PMID:26797053, PMID:32164484); it localizes to the mitochondria-associated membrane to fold StAR and support steroidogenesis (PMID:28275724); it functions at the cell surface as a signaling receptor for ligands including integrin β1, IGF-1R, α2-macroglobulin, and viral spike proteins, activating PI3K/AKT and JAK/STAT pathways (PMID:19331544, PMID:30914477, PMID:34713304, PMID:34615619); and it translocates to the nucleus to bind and inhibit the transcriptional repressor ID2, driving an invasive gene expression program (PMID:37487081). These activities make HSPA5 an oncogenic dependency that stabilizes GPX4 to confer ferroptosis resistance (PMID:28130223, PMID:31519193), promotes PI3K/AKT/mTOR signaling and Kras-driven tumorigenesis (PMID:33931739, PMID:21937694), and is essential for myelinating cell survival and tissue development (PMID:26631473).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Established that the BiP ortholog is an autonomous ATPase whose nucleotide state drives conformational change, the biochemical basis for chaperone cycling.

    Evidence Purification of yeast Kar2 with ATPase and protease-susceptibility assays

    PMID:1325440

    Open questions at the time
    • Did not define how ATP cycling couples to client binding in the mammalian protein
    • Co-chaperone requirements unresolved
  2. 1999 High

    Defined the core chaperone role: BiP binds nascent proteins entering the ER and triages aberrant ones for ERAD, framing it as essential to ER proteostasis.

    Evidence Synthesis of genetic and biochemical studies in yeast and mammalian cells; co-IP with AMPA receptor subunits from brain

    PMID:10461883 PMID:10597629

    Open questions at the time
    • Did not establish substrate specificity rules
    • Native client repertoire only partially defined
  3. 1998 High

    Demonstrated that BiP ATPase activity is functionally required for folding of a specific client, linking the enzymatic cycle to physiological maturation.

    Evidence ATPase-dead T37G mutant overexpression and co-IP with APP in HEK293 cells

    PMID:9748217

    Open questions at the time
    • Single client; generality to other secretory proteins not tested here
  4. 2000 High

    Identified MTJ1 as a functional DnaJ co-chaperone that stimulates BiP ATPase, explaining how BiP activity is spatially and substrate-directed.

    Evidence In vitro ATPase and binding assays with HPD-motif mutagenesis

    PMID:10777498

    Open questions at the time
    • Full set of ER J-proteins coordinating BiP not enumerated
    • Nucleotide exchange factor role separate
  5. 2005 High

    Consolidated the binding-release model in which BiP sequesters IRE1, PERK, and ATF6 and is titrated away by unfolded load, establishing BiP as the master UPR sensor.

    Evidence Co-IP, loss-of-function, and promoter/expression assays across labs; ATF6 retention/dissociation mechanism

    PMID:12110159 PMID:15804610

    Open questions at the time
    • Whether sensor regulation is purely competitive or allosteric not fully resolved
    • Stoichiometry of BiP across the three sensors unclear
  6. 2009 Medium

    Revealed that cell-surface GRP78 acts as a multifunctional signaling receptor and that its promoter is repressed by HDAC1, expanding GRP78 beyond an ER chaperone.

    Evidence Cell-surface binding/signaling assays with multiple ligands; ChIP of HDAC1 on the Grp78 promoter; Cab45S domain-mapping co-IP

    PMID:19331544 PMID:19417144 PMID:24810055

    Open questions at the time
    • Mechanism of GRP78 surface translocation not defined
    • Many receptor functions described in review without unified structural model
  7. 2015 High

    Showed HSPA5 stability is set by competing ubiquitin ligases and deacetylation, establishing post-translational control of chaperone levels.

    Evidence Site-specific mutagenesis (K447, K353), GP78 ubiquitination assays, HDAC6 knockdown

    PMID:26119938

    Open questions at the time
    • Physiological triggers selecting degradation vs. stabilization unclear
    • Crosstalk between K353 acetylation and other modifications not mapped
  8. 2016 High

    Defined acetylation-controlled exosomal secretion and FOXM1-driven transcriptional and cytosolic arginylation routes, broadening HSPA5 output to autophagy and intercellular signaling.

    Evidence K633Q mimetic mutagenesis with VPS34 co-IP and exosome fractionation; ChIP and promoter mapping of FOXM1; in vitro arginylation and SQSTM1 ZZ-domain interaction with autophagy flux

    PMID:26797053 PMID:27034162 PMID:27460191

    Open questions at the time
    • How cytosolic relocalization is triggered remains partially defined
    • In vivo relevance of exosomal HSPA5 not established here
  9. 2017 High

    Connected HSPA5 to ferroptosis resistance and to extra-ER folding roles, establishing it as a stabilizer of GPX4 and a MAM steroidogenic factor.

    Evidence Co-IP and GPX4 stability assays in PDAC; MAM fractionation and StAR folding with knockdown; in vitro and in vivo PrPSc clearance

    PMID:28130223 PMID:28275724 PMID:28333162

    Open questions at the time
    • Mechanism by which HSPA5 protects GPX4 from degradation not structurally defined
    • MAM targeting signal unknown
  10. 2019 High

    Demonstrated genetic and physiological consequences of BiP availability across ferroptosis feedback, fibrosis, vascular permeability, circadian rhythm, and the central requirement of excess BiP to avoid proteotoxicity.

    Evidence PERK→ATF4→HSPA5→GPX4 epistasis; csGRP78–integrin β1 co-IP and diabetic models; SubAB selective cleavage and LPS lung injury; BiP overexpression circadian assays; IgM heavy-chain proteostasis with HRD1/ATF6 ablation

    PMID:30765717 PMID:30869076 PMID:30888851 PMID:30914477 PMID:31519193

    Open questions at the time
    • Distinct intracellular vs. surface pools incompletely separated mechanistically
    • How BiP excess is sensed quantitatively not defined
  11. 2020 High

    Resolved AMPylation and arginylation as conditional activity switches and added membrane-lipid binding and chaperone hierarchy, refining how HSPA5 is reprogrammed under stress.

    Evidence In vitro AMPylation kinetics at Thr518/Thr366 by HYPE; R-HSPA5 escorting ubiquitinated AKT to autophagy in MUL1-KO cells; liposome binding/oligomerization assays; GRP94→BiP client-transfer epistasis; NLRP6 domain-mapped ubiquitination

    PMID:32164484 PMID:32682010 PMID:32725381 PMID:33942205 PMID:35905823

    Open questions at the time
    • In vivo significance of AMPylation site selectivity unclear
    • Lipid-binding role in surface translocation not directly linked
  12. 2021 High

    Established HSPA5 as an oncogenic dependency and immune/viral interaction node, showing genetic requirement for Kras-driven tumors, macrophage polarization, and SARS-CoV-2 spike binding.

    Evidence Conditional Grp78 KO × KrasLSL-G12D models with human cell knockdown; macrophage knockdown with JAK/STAT and IGF-1R co-IP; spike–GRP78 co-IP

    PMID:33931739 PMID:34615619 PMID:34713304

    Open questions at the time
    • Whether tumor dependency reflects ER chaperone or surface/signaling functions not separated
    • Spike–GRP78 contribution to infection in vivo not quantified
  13. 2023 High

    Identified nuclear GRP78 as a direct regulator of transcription via ID2 inhibition and refined acetylation control of ferroptosis, completing a picture of compartment-specific functions.

    Evidence NLS mutagenesis, nuclear fractionation, GRP78–ID2 co-IP, migration assays; EP300/HDAC6 acetylation at K353 with ferroptosis readouts

    PMID:37487081 PMID:37696842

    Open questions at the time
    • Signal triggering nuclear translocation incompletely defined
    • Direct DNA-binding vs. cofactor-only role of nuclear GRP78 unresolved
  14. 2024 Medium

    Added palmitoylation as a stability/localization switch, showing ZDHHC9 modification retains BiP in the ER and suppresses UPR to promote cancer chemoresistance.

    Evidence ZDHHC9–BiP co-IP, Cys420 palmitoylation assay, knockdown, UPR and localization analysis

    PMID:39002690

    Open questions at the time
    • Single lab; depalmitoylase counter-enzyme not identified
    • Interplay with ubiquitination/acetylation network not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the various HSPA5 modifications and relocalization events are integrated into a single decision logic—and how each subcellular pool is selectively targeted—remains unresolved.
  • No unified model linking modification state to ER/cytosol/surface/nuclear partitioning
  • Structural basis of non-canonical receptor and transcriptional functions undefined
  • Quantitative rules of BiP-availability sensing of the UPR not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 5 GO:0140657 ATP-dependent activity 4 GO:0060089 molecular transducer activity 3 GO:0140313 molecular sequestering activity 3 GO:0001618 virus receptor activity 2 GO:0008289 lipid binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005886 plasma membrane 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 2
Partners
ATF6GP78GPX4ID2IRE1ITGB1MTJ1OTUD3

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 BiP/GRP78 binds newly-synthesized proteins as they are translocated into the ER lumen, maintaining them in a folding-competent state; it is an essential component of the ER translocation machinery and plays a role in retrograde transport (ERAD) of aberrant proteins destined for proteasomal degradation. Review synthesizing genetic and biochemical studies in yeast and mammalian cells Seminars in cell & developmental biology High 10597629
1992 Purified yeast BiP/Kar2 (ortholog of HSPA5) is active as a homodimer and exhibits intrinsic ATPase activity; the ADP-bound form is more protease-resistant than the ATP-bound form, indicating ATP-dependent conformational changes. Protein purification, ATPase assay, protease susceptibility assay The Journal of biological chemistry High 1325440
1998 BiP/GRP78 co-precipitates with amyloid precursor protein (APP) in the ER, transiently interacting with it; expression of an ATPase-dead mutant (T37G) of GRP78 nearly completely blocks APP maturation and reduces secretion of APPs, Aβ40, and Aβ42, demonstrating that GRP78 ATPase activity is required for APP folding and processing. Metabolic labeling, co-immunoprecipitation, ATPase mutant overexpression in HEK293 cells The Journal of biological chemistry High 9748217
2000 Murine BiP/GRP78 physically interacts with the lumenal J domain of the transmembrane protein MTJ1; this interaction stimulates BiP ATPase activity at stoichiometric concentrations and is abolished by the conserved HPD→HPQ substitution in MTJ1, demonstrating MTJ1 is a functional DnaJ co-chaperone for BiP. In vitro ATPase assay, binding studies, site-directed mutagenesis of HPD motif The Journal of biological chemistry High 10777498
2002 BiP/GRP78 binds to ATF6 and retains it in the ER; dissociation of BiP from ATF6 upon ER stress allows ATF6 to translocate to the Golgi for proteolytic activation, identifying BiP as the key sensor that couples ER folding capacity to ATF6 activation. Genetic and biochemical analysis (reviewed mechanistic study) Developmental cell Medium 12110159
2005 GRP78/BiP controls the activation of the three transmembrane ER stress sensors (IRE1, PERK, ATF6) through a binding-release mechanism: under non-stress conditions BiP keeps sensors inactive; accumulation of unfolded proteins titrates BiP away, freeing sensors to activate the UPR. Promoter assays, mRNA/protein quantification, established mechanistic framework Methods (San Diego, Calif.) High 15804610
2006 MDA-7/IL-24 physically interacts with BiP/GRP78 through its C and F helices; the complex localizes in the ER and activates p38 MAPK and GADD gene expression, leading to cancer-selective apoptosis. Deletion and mutational analysis, co-immunoprecipitation, subcellular localization Cancer research Medium 16912197
2009 Cell-surface GRP78 functions as a signaling receptor: binding of activated α2-macroglobulin activates AKT to suppress apoptosis and upregulates NF-κB; interaction with Cripto nullifies TGF-β/Smad2/3 signaling; interaction with Par-4 or plasminogen kringle 5 promotes apoptosis; association with tissue factor inhibits procoagulant activity. Cell-surface binding assays, signaling pathway analysis, co-immunoprecipitation Antioxidants & redox signaling Medium 19331544
2009 Cab45S specifically binds to the nucleotide-binding domain (NBD) of GRP78/BiP and stabilizes the GRP78-IRE1 interaction, thereby inhibiting ER stress-induced IRE1 activation and downstream JNK phosphorylation and apoptosis. Co-immunoprecipitation, domain-mapping, siRNA knockdown, functional apoptosis assays Cell death & disease Medium 24810055
2015 GP78 (E3 ubiquitin ligase) interacts with the C-terminal region of HSPA5 and mediates its polyubiquitination at lysine 447 (K447), targeting HSPA5 for proteasomal degradation; HDAC6 deacetylates HSPA5 at K353, which is required for GP78-mediated ubiquitination at K447. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K447, K353), HDAC6 knockdown Oncogene High 26119938
2016 HDAC6 deacetylation of HSPA5 at K633 promotes its secretion into exosomes via the multivesicular body (MVB) pathway; acetylated HSPA5 (mimicked by K633Q mutation) binds VPS34 and prevents MVB sorting, blocking secretion. HDAC inhibitor treatment, acetylation-mimetic mutagenesis (K633Q), VPS34 co-IP, exosome fractionation Scientific reports Medium 27460191
2016 FOXM1 directly binds to and transactivates the HSPA5 promoter at a site mapped between −1019 and −1012 bp, upregulating HSPA5 expression; HSPA5 depletion attenuates FOXM1-driven colorectal cancer cell migration and invasion, acting downstream through cell-surface HSPA5 and MMP2/9 activity. Promoter-binding assay, chromatin immunoprecipitation, luciferase reporter, siRNA knockdown, invasion assays Oncotarget Medium 27034162
2016 N-terminal arginylation (Nt-arginylation) of HSPA5 by ATE1 arginyltransferase generates R-HSPA5 in the cytosol; R-HSPA5's N-terminal arginine is recognized by the ZZ domain of SQSTM1/p62, inducing SQSTM1 conformational change, self-polymerization, and LC3 interaction, thereby directing misfolded protein cargoes to autophagosomes for lysosomal degradation. In vitro arginylation, co-immunoprecipitation, autophagy flux assays, domain-specific interaction mapping Autophagy High 26797053
2017 HSPA5 binds directly to GPX4 protein and protects it from degradation; ATF4-induced HSPA5 upregulation stabilizes GPX4 protein levels, thereby inhibiting lipid peroxidation and conferring ferroptosis resistance in pancreatic ductal adenocarcinoma cells. Co-immunoprecipitation, siRNA/pharmacological inhibition, GPX4 protein stability assays, in vitro and in vivo ferroptosis assays Cancer research High 28130223
2017 GRP78 localizes to the mitochondria-associated ER membrane (MAM) where it folds steroidogenic acute regulatory protein (StAR); GRP78 knockdown drastically reduces StAR expression and steroidogenic activity, identifying GRP78 as an acute regulator of steroidogenesis at the MAM. GRP78 knockdown, subcellular fractionation (MAM isolation), StAR activity assays, protein folding experiments Science advances Medium 28275724
2017 GRP78/BiP directly interacts with misfolded PrPSc in vitro; recombinant GRP78 incubated with PrPSc reduces protease-resistant PrPSc in a dose-dependent manner; in cells, BiP expression levels inversely correlate with prion replication; in vivo, reduced GRP78 expression accelerates prion pathogenesis. In vitro incubation of recombinant GRP78 with PrPSc, cell culture prion replication assay, co-immunoprecipitation, conditional knockout mouse model Scientific reports High 28333162
2018 MUL1 (mitochondrial E3 ubiquitin ligase) directly ubiquitinates HSPA5 at lysine 446 (K446) via K48-linked ubiquitin chains, promoting HSPA5 proteasomal degradation; this leads to lysosomal inhibition and cytotoxicity in head and neck cancer cells. K446 site mutagenesis, ubiquitination assays, CRISPR/Cas9 MUL1 knockout, xenograft model Autophagy High 29260979
2019 The deubiquitylase OTUD3 interacts with GRP78, removes its ubiquitin chains, and stabilizes GRP78 protein; OTUD3 knockdown reduces GRP78 protein levels and suppresses lung cancer cell growth and migration. Co-immunoprecipitation, deubiquitylation assay, OTUD3 knockdown, mouse lung adenocarcinoma model Nature communications High 31266968
2019 DHA-induced ER stress activates the PERK→ATF4→HSPA5 pathway in glioma cells; HSPA5 upregulation then increases GPX4 expression and activity, neutralizing lipid peroxidation and protecting cells from ferroptosis via a negative feedback loop. siRNA knockdown of PERK/ATF4/HSPA5, GPX4 activity assays, ROS/lipid peroxidation measurement, in vitro and in vivo models Journal of experimental & clinical cancer research Medium 31519193
2019 BiP/GRP78 overexpression strengthens circadian rhythm oscillation amplitude; adequate BiP levels preemptively prevent ER stress in collagen-synthesizing fibroblasts, thereby preventing UPR activation and maintaining circadian gene expression. BiP overexpression, chemical chaperone treatment, circadian reporter assays in fibroblasts and tendon tissue FASEB journal Medium 30888851
2019 Inadequate BiP availability is the defining molecular event of proteostatic ER stress: conditions that prevent restoration of excess BiP over unfolded substrate (μs heavy chain) — including abrogation of HRD1-mediated ERAD or the ATF6α branch of UPR — lead to proteotoxicity; removal of the BiP-sequestering CH1 domain from µs tolerates the same conditions without toxicity. Inducible expression of secretory IgM heavy chain, genetic ablation of ERAD (HRD1 KO) and UPR branches, electron microscopy eLife High 30869076
2019 Cell-surface GRP78 (csGRP78) interacts with integrin β1 on kidney mesangial cells under high-glucose conditions, activating focal adhesion kinase and downstream PI3K/AKT signaling, which drives extracellular matrix protein synthesis; both N- and C-termini of csGRP78 are required for this profibrotic response. Cell-surface biotinylation, co-immunoprecipitation of csGRP78 with integrin β1, siRNA knockdown, signaling assays, diabetic mouse models The Journal of biological chemistry High 30914477
2019 Intracellular (not cell-surface) BiP/GRP78 mediates thrombin-induced Ca2+ signaling and endothelial permeability, as well as NF-κB-dependent upregulation of VCAM-1, ICAM-1, IL-6, and IL-8; specific inactivation of intracellular BiP by the protease SubAB or a dominant-negative mutant abolishes these responses in vitro and reduces LPS-induced lung injury in vivo. SubAB-mediated selective BiP cleavage, dominant-negative BiP gene transfer, LPS-inhalation mouse model, Ca2+ imaging, permeability assays Scientific reports High 30765717
2020 ATE1-mediated arginylation of HSPA5 (generating R-HSPA5) is induced by ROS upon proteasome inhibition; R-HSPA5 binds K48-linked polyubiquitinated AKT (sequentially ubiquitinated at K284 then K214 by MUL1) and escorts it to the autophagy-lysosome pathway for degradation; USP7 antagonizes this by deubiquitinating AKT. Co-immunoprecipitation, ubiquitin linkage analysis, ATE1 overexpression, MUL1 knockout cells, autophagy flux inhibitors Autophagy High 32164484
2020 HSPA5 interacts with negatively charged phospholipids (POPS, cardiolipin) via both its N- and C-terminal domains; membrane binding promotes HSPA5 oligomerization through intermolecular disulfide bonds, with the N-terminal domain playing a critical role in this process. Liposome binding assays with purified full-length and truncated HSPA5, disulfide bond analysis Cell stress & chaperones Medium 32725381
2021 HSPA5/GRP78 mediates Pneumocystis carinii binding and colonization of lung epithelial cells; affinity chromatography identified HSPA5 as the receptor, and CHO cells overexpressing HSPA5 bound Pc organisms more than parental cells, confirming direct Pc-HSPA5 protein interaction. Affinity chromatography, overexpression binding assay in CHO cells, primary rat airway epithelial cells Journal of medical microbiology Medium 30328808
2020 NLRP6 binds to GRP78 through its Pyrin domain (interaction mediated via the SBD domain of GRP78), promotes GRP78 polyubiquitination, and thereby suppresses gastric cancer cell proliferation, cell cycle progression, migration, and tumorigenesis. Flag-tagged immunoprecipitation, LC/MS proteomics, ubiquitination assays, domain mapping, overexpression/knockdown, xenograft model Experimental cell research Medium 32682010
2021 HSPA5/GRP78 is required for KrasG12D-driven lung adenocarcinoma initiation and progression; GRP78 haploinsufficiency in floxed mouse models suppresses KrasG12D-mediated lung tumor progression, prolongs survival, and GRP78 knockdown in human lung cancer cells (KrasG12D/+) activates UPR and apoptotic markers. Conditional knockout mouse model (floxed Grp78 × KrasLSL-G12D), siRNA knockdown in human lung cancer cells, tumor histology, survival analysis Oncogene High 33931739
2021 GRP78 knockdown in macrophages promotes M1 differentiation and suppresses M2 polarization via the JAK/STAT pathway; GRP78 regulates IGF-1 secretion by macrophages and, in response to IGF-1, GRP78 translocates to the plasma membrane and associates with the IGF-1 receptor to promote M2 polarization. GRP78 knockdown, cytokine secretion assay, JAK/STAT pathway analysis, IGF-1 neutralization, subcellular fractionation, co-immunoprecipitation, conditioned medium experiments Cellular and molecular life sciences Medium 34713304
2021 SARS-CoV-2 spike protein physically interacts with cell-surface GRP78, promoting binding and accumulation in ACE2-expressing cells; GRP78 expression in adipose tissue is upregulated by hyperinsulinemia partly through the XBP-1s transcription factor. Co-immunoprecipitation of spike protein with GRP78, cell binding assays, gene expression analysis in adipocytes Diabetes Medium 34615619
2021 HYPE/FicD AMPylates BiP/GRP78 at Thr518 (structurally preferred) and Thr366; AMPylation at Thr366 vs. Thr518 differentially affects BiP ATPase activity; HYPE preferentially de-AMPylates wild-type adenylylated BiP; HYPE does not adenylylate UPR accessory proteins like ERdJ6. In vitro AMPylation kinetic assays, molecular docking, ATPase activity assays, binding efficiency measurements Cell stress & chaperones High 33942205
2022 HspA5/GRP78 directly binds the RNA-recognition motif (RRM) domain of TDP-43 in a pulldown assay using recombinant proteins; overexpression of HspA5 in a Drosophila TDP-43 toxicity model rescues TDP-43-induced lethality, indicating HspA5 mitigates TDP-43 proteotoxicity. BioID proximity labeling, recombinant protein pulldown, Drosophila overexpression rescue assay Scientific reports Medium 35581326
2022 GRP94 acts upstream of BiP in ER protein remodeling under strong denaturing conditions: Grp94 binds misfolded proteins in an ATP-independent manner to prevent aggregation, then releases them via ATP binding (without hydrolysis) for subsequent refolding by the BiP system; direct Grp94-BiP interaction is not required for client transfer. In vitro refolding assays with purified proteins, ATP binding/hydrolysis mutants, aggregation prevention assays Journal of molecular biology High 35905823
2023 Nuclear GRP78 regulates gene expression by interacting with and inhibiting the transcriptional repressor ID2, promoting expression of genes involved in cell migration and invasion; a nuclear localization signal in GRP78 is critical for its stress-induced translocation to the nucleus. NLS mutagenesis, nuclear fractionation, co-immunoprecipitation of GRP78-ID2, gene expression profiling, cancer cell migration assays Proceedings of the National Academy of Sciences of the United States of America High 37487081
2023 EP300 acetyltransferase acetylates HSPA5 at K353, causing loss of its ability to inhibit lipid peroxidation and ferroptotic cell death in pancreatic cancer cells; HDAC6 opposes this by deacetylating HSPA5, limiting ferroptosis sensitivity. In vitro acetylation assay, K353 site mutagenesis, EP300 and HDAC6 genetic/pharmacological manipulation, ferroptosis assays (lipid ROS, cell death) Scientific reports Medium 37696842
2024 ZDHHC9 palmitoylates GRP78/BiP at cysteine 420 (Cys420), enhancing BiP protein stability and maintaining its ER localization; this palmitoylation inhibits the unfolded protein response and promotes bladder cancer progression and chemoresistance. Co-immunoprecipitation of ZDHHC9-Bip, palmitoylation assay at Cys420, ZDHHC9 knockdown, UPR marker analysis, subcellular localization Cancer letters Medium 39002690
2009 HDAC1 binds to the Grp78 promoter under non-stress conditions (demonstrated by ChIP) and represses its transcription; ER stress causes HDAC1 dissociation from the promoter, allowing GRP78 induction; overexpression of GRP78 confers resistance to HDAC inhibitor-induced apoptosis, while GRP78 knockdown sensitizes cancer cells. Chromatin immunoprecipitation (ChIP), promoter mutational analysis, HDAC1 overexpression/siRNA knockdown, apoptosis assays Molecular cancer therapeutics High 19417144
2011 GRP78 promotes PI3K/AKT/mTOR oncogenic signaling in the hematopoietic system; heterozygous knockout of GRP78 in PTEN-null mice restores the hematopoietic stem cell population, suppresses leukemic blast expansion, and potently inhibits AKT/mTOR activation in PTEN-null BM cells. Biallelic conditional knockout mouse model (GRP78 × PTEN), flow cytometry, AKT/mTOR phosphorylation assays, GRP78 knockdown in leukemia cell lines Blood High 21937694
2012 IGF-1 receptor signaling regulates GRP78 expression via the PI3K/AKT/mTORC1 axis (independently of FOXO1 and the canonical UPR); IGF-1 receptor-null MEFs express 80% less GRP78 but remain capable of activating the UPR when needed. IGF-1R knockout and overexpression MEFs, mTORC1 and PI3K inhibitors, FOXO1 knockdown, calorie restriction in mice Journal of cellular physiology Medium 22422508
1999 BiP/GRP78 co-immunoprecipitates with AMPA receptor subunits (GluR1, GluR2/3, GluR4) from rat forebrain membranes; both BiP and calnexin are detected in dendrites of hippocampal pyramidal neurons co-localizing with AMPA receptor subunits, consistent with an ER chaperone role in AMPA receptor assembly. Co-immunoprecipitation from native brain membranes, western blotting, immunocytochemistry Journal of neurochemistry Medium 10461883
2014 Hspa5/GRP78 is essential for pronephros (kidney) formation in Xenopus; knockdown with morpholino antisense oligonucleotides inhibits pronephric marker gene expression (lhx1, pax2, atp1b1) by attenuating retinoic acid (RA) signaling and reducing Lhx1 expression; co-injection of lhx1 mRNA partially rescues the phenotype. Morpholino knockdown in Xenopus embryos, animal cap explant assay, rescue by mRNA injection, retinoic acid-responsive gene expression The Journal of biological chemistry Medium 25398881
2015 BiP/GRP78 is critical for myelinating cell survival; conditional knockout of BiP in oligodendrocytes causes tremors, ataxia, and premature death in developing mice, and triggers oligodendrocyte loss and myelin abnormalities; adult knockout produces severe neurological symptoms; BiP haploinsufficiency exacerbates EAE-induced oligodendrocyte loss. Oligodendrocyte-specific conditional BiP knockout mouse, Schwann cell-specific conditional BiP knockout, EAE model, neuropathology The Journal of neuroscience High 26631473
2015 Increased BiP expression in Alzheimer's disease model (Tg2576) brains induces tau hyperphosphorylation by activating GSK-3β and increasing the association of tau with GSK-3β; SIL1 (BiP co-chaperone) deficiency is observed in Tg2576 brains and under ER stress, and SIL1 overexpression reduces BiP-induced tau hyperphosphorylation and GSK-3β activation. Bip-EGFP transfection in HEK293/tau cells, co-immunoprecipitation of tau-GSK3β, SIL1 overexpression, transgenic mouse brain analysis Molecular neurobiology Medium 25575678
2013 GRP78/BiP is recruited into androgen receptor (AR) inclusions in embryonic stem cells (ESCs) upon androgen stimulation; GRP78 dissociates from ATF6 and instead acts as an AR-interacting protein; GRP78 overexpression suppresses AR aggregate ubiquitination and ameliorates misfolded AR-mediated cytopathology, while GRP78 knockdown increases AR aggregates and caspase-3 activity. Co-immunoprecipitation of GRP78-AR, immunofluorescence co-localization, GRP78 overexpression/knockdown, ubiquitination assay, caspase-3 activity Cell death & disease Medium 23618905

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods (San Diego, Calif.) 850 15804610
2006 Stress induction of GRP78/BiP and its role in cancer. Current molecular medicine 521 16472112
2019 GRP78: A cell's response to stress. Life sciences 510 30978349
2017 HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer research 478 28130223
1999 Role and regulation of the ER chaperone BiP. Seminars in cell & developmental biology 421 10597629
1994 The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications. Critical reviews in eukaryotic gene expression 304 7987045
2019 Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells. Journal of experimental & clinical cancer research : CR 268 31519193
2017 HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene 240 28286085
2009 GRP78: a multifunctional receptor on the cell surface. Antioxidants & redox signaling 221 19331544
1994 BiP (GRP78), an essential hsp70 resident protein in the endoplasmic reticulum. Experientia 205 7988659
2017 GRP78 at the Centre of the Stage in Cancer and Neuroprotection. Frontiers in neuroscience 184 28424579
2008 GRP78: a chaperone with diverse roles beyond the endoplasmic reticulum. Histology and histopathology 159 18785123
2009 Functions and pathologies of BiP and its interaction partners. Cellular and molecular life sciences : CMLS 156 19151922
1998 The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. The Journal of biological chemistry 155 9748217
2010 Roles of GRP78 in physiology and cancer. Journal of cellular biochemistry 147 20506407
2006 BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. Cancer research 113 16912197
2019 The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis. Nature communications 110 31266968
2023 ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator. Proceedings of the National Academy of Sciences of the United States of America 107 37487081
2020 GRP78 targeting: Hitting two birds with a stone. Life sciences 90 32841659
2021 GRP78 in lung cancer. Journal of translational medicine 87 33743739
2009 Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. Molecular cancer therapeutics 84 19417144
2000 Interaction of murine BiP/GRP78 with the DnaJ homologue MTJ1. The Journal of biological chemistry 83 10777498
2017 Mitochondrial metabolic regulation by GRP78. Science advances 80 28275724
2015 GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease. Journal of cellular physiology 80 25546329
2017 The Endoplasmic Reticulum Chaperone GRP78/BiP Modulates Prion Propagation in vitro and in vivo. Scientific reports 79 28333162
2014 Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. Cell death & disease 78 24810055
2010 GRP78 signaling hub a receptor for targeted tumor therapy. Advances in genetics 77 20807604
2011 Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood 76 21937694
2021 Glucose-regulated protein (GRP78) is an important cell surface receptor for viral invasion, cancers, and neurological disorders. IUBMB life 75 33960608
2018 HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer. Autophagy 69 29260979
2007 A role for the molecular chaperone protein BiP/GRP78 in Drosophila sleep homeostasis. Sleep 69 17552370
2016 New anti-cancer molecules targeting HSPA5/BIP to induce endoplasmic reticulum stress, autophagy and apoptosis. Autophagy 67 27791469
2015 Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer. Oncogene 64 26119938
2002 BiP binding keeps ATF6 at bay. Developmental cell 64 12110159
2022 The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 63 35320827
2020 Targeting the GRP78 Pathway for Cancer Therapy. Frontiers in medicine 60 32850882
2016 Acetylation modification regulates GRP78 secretion in colon cancer cells. Scientific reports 60 27460191
2019 Pharmacological effectors of GRP78 chaperone in cancers. Biochemical pharmacology 59 30831072
2019 Inadequate BiP availability defines endoplasmic reticulum stress. eLife 59 30869076
2021 Linking cell-surface GRP78 to cancer: From basic research to clinical value of GRP78 antibodies. Cancer letters 57 34637844
2021 Possible Involvement of Adipose Tissue in Patients With Older Age, Obesity, and Diabetes With SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19. Diabetes 52 34615619
2009 Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced interleukin-6 upregulation in the macrophage. Toxicological sciences : an official journal of the Society of Toxicology 52 19336499
2009 Knockdown of ERp57 increases BiP/GRP78 induction and protects against hyperoxia and tunicamycin-induced apoptosis. American journal of physiology. Lung cellular and molecular physiology 51 19411306
1999 Calnexin and the immunoglobulin binding protein (BiP) coimmunoprecipitate with AMPA receptors. Journal of neurochemistry 49 10461883
2016 Cell surface GRP78 as a biomarker and target for suppressing glioma cells. Scientific reports 48 27713511
2015 ER Chaperone BiP/GRP78 Is Required for Myelinating Cell Survival and Provides Protection during Experimental Autoimmune Encephalomyelitis. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 26631473
1992 Purification and characterization of BiP/Kar2 protein from Saccharomyces cerevisiae. The Journal of biological chemistry 46 1325440
2023 New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19. Frontiers in immunology 43 37275848
2019 Selective Inactivation of Intracellular BiP/GRP78 Attenuates Endothelial Inflammation and Permeability in Acute Lung Injury. Scientific reports 42 30765717
2007 Cloning and expression of glucose regulated protein 78 (GRP78) in Fenneropenaeus chinensis. Molecular biology reports 42 18038268
2019 Cell surface expression of 78-kDa glucose-regulated protein (GRP78) mediates diabetic nephropathy. The Journal of biological chemistry 41 30914477
2016 FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation. Oncotarget 40 27034162
2020 Crosstalk between HSPA5 arginylation and sequential ubiquitination leads to AKT degradation through autophagy flux. Autophagy 39 32164484
2002 Kinetic model of BiP- and PDI-mediated protein folding and assembly. Journal of theoretical biology 37 11851365
2022 HSPA5 repressed ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Neoplasma 36 35723198
2020 UBE2T promotes glioblastoma invasion and migration via stabilizing GRP78 and regulating EMT. Aging 36 32491994
2017 Roles of Grp78 in Female Mammalian Reproduction. Advances in anatomy, embryology, and cell biology 36 28389754
2014 HKH40A downregulates GRP78/BiP expression in cancer cells. Cell death & disease 36 24853418
2021 GRP78 facilitates M2 macrophage polarization and tumour progression. Cellular and molecular life sciences : CMLS 35 34713304
2019 GRP78/BIP/HSPA5 as a Therapeutic Target in Models of Parkinson's Disease: A Mini Review. Advances in pharmacological sciences 35 30949202
2016 Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP. Autophagy 34 26797053
2012 GRP78/BiP is a novel downstream target of IGF-1 receptor mediated signaling. Journal of cellular physiology 34 22422508
2023 HSPA5 Promotes the Proliferation, Metastasis and Regulates Ferroptosis of Bladder Cancer. International journal of molecular sciences 33 36982218
2020 Zika virus envelope - heat shock protein A5 (GRP78) binding site prediction. Journal of biomolecular structure & dynamics 33 32579073
2024 ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer progression. Cancer letters 32 39002690
2021 Endoplasmic reticulum chaperone GRP78/BiP is critical for mutant Kras-driven lung tumorigenesis. Oncogene 31 33931739
2015 SIL1 Rescued Bip Elevation-Related Tau Hyperphosphorylation in ER Stress. Molecular neurobiology 31 25575678
2014 GRP78 mediates cell growth and invasiveness in endometrial cancer. Journal of cellular physiology 31 24526410
2022 Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology. Scientific reports 30 35581326
2023 EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer. Scientific reports 29 37696842
2020 Zika virus subversion of chaperone GRP78/BiP expression in A549 cells during UPR activation. Biochimie 29 32464166
2014 Heat shock 70-kDa protein 5 (Hspa5) is essential for pronephros formation by mediating retinoic acid signaling. The Journal of biological chemistry 29 25398881
2020 Interaction of HSPA5 (Grp78, BIP) with negatively charged phospholipid membranes via oligomerization involving the N-terminal end domain. Cell stress & chaperones 28 32725381
2013 Targeting GRP78 and antiestrogen resistance in breast cancer. Future medicinal chemistry 28 23734687
2020 NLRP6 suppresses gastric cancer growth via GRP78 ubiquitination. Experimental cell research 26 32682010
2020 Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice. Scientific reports 26 33184425
2019 Preservation of circadian rhythms by the protein folding chaperone, BiP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 30888851
2021 COVID19 associated mucormycosis: Is GRP78 a possible link? Journal of infection and public health 23 34538732
2018 The Interplay between Glucose-Regulated Protein 78 (GRP78) and Steroids in the Reproductive System. International journal of molecular sciences 23 29932125
2001 Isolation, expression, and characterization of fully functional nontoxic BiP/GRP78 mutants. Protein expression and purification 23 11388813
2023 Identification of heat shock protein family A member 5 (HSPA5) targets involved in nonalcoholic fatty liver disease. Genes and immunity 21 37156995
2023 GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells. Cell reports. Medicine 21 37992682
2017 AAV delivery of GRP78/BiP promotes adaptation of human RPE cell to ER stress. Journal of cellular biochemistry 20 28782832
2010 Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3. International journal of cancer 20 19626590
2024 Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways. Journal of cellular and molecular medicine 19 38494858
2021 GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy. Scientific reports 19 34789798
2015 Involvement of GRP78 in the Resistance of Ovarian Carcinoma Cells to Paclitaxel. Asian Pacific journal of cancer prevention : APJCP 19 25921171
2012 Thapsigargin down-regulates protein levels of GRP78/BiP in INS-1E cells. Journal of cellular biochemistry 19 22189689
2009 The Par-4-GRP78 TRAIL, more twists and turns. Cancer biology & therapy 19 19823030
2021 Kinetic and structural parameters governing Fic-mediated adenylylation/AMPylation of the Hsp70 chaperone, BiP/GRP78. Cell stress & chaperones 18 33942205
2013 Androgen receptor inclusions acquire GRP78/BiP to ameliorate androgen-induced protein misfolding stress in embryonic stem cells. Cell death & disease 18 23618905
2020 Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma. Expert review of hematology 17 32990063
2007 Activation profiles of HSPA5 during the glomerular mesangial cell stress response to chemical injury. Cell stress & chaperones 16 17915553
1996 Bip/GRP78 but not calnexin associates with a precursor of glycosylphosphatidylinositol-anchored protein. The Biochemical journal 16 8687409
2025 Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy. Proceedings of the National Academy of Sciences of the United States of America 15 40699920
2023 DJ-1 inhibits ferroptosis in cerebral ischemia-reperfusion via ATF4/HSPA5 pathway. Neurochemistry international 15 37820776
2022 Grp94 Works Upstream of BiP in Protein Remodeling Under Heat Stress. Journal of molecular biology 15 35905823
2018 Binding of Pneumocystis carinii to the lung epithelial cell receptor HSPA5 (GRP78). Journal of medical microbiology 15 30328808
2012 Co-silencing of Birc5 (survivin) and Hspa5 (Grp78) induces apoptosis in hepatoma cells more efficiently than single gene interference. International journal of oncology 15 22581315
2017 Expression and release of glucose-regulated protein-78 (GRP78) in multiple myeloma. Oncotarget 14 28915587

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