Affinage

HYOU1

Hypoxia up-regulated protein 1 · UniProt Q9Y4L1

Length
999 aa
Mass
111.3 kDa
Annotated
2026-06-10
86 papers in source corpus 32 papers cited in narrative 32 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

HYOU1 (ORP150/GRP170) is an ER-resident member of the HSP70 superfamily that functions as a stress-inducible molecular chaperone safeguarding secretory protein folding and ER proteostasis (PMID:9020069, PMID:14674765). Originally isolated as a ~150 kDa hypoxia-induced ER stress protein in astrocytes, it is transcriptionally upregulated by oxygen deprivation and its loss accelerates hypoxia-specific apoptosis, defining a cytoprotective role under ER stress (PMID:8617779, PMID:10037731). Biochemically it acts as an ATP-independent holdase: it binds unfolded—but not folded—secretory substrates and maintains denatured proteins in a soluble, refolding-competent state through two distinct substrate-binding regions, a β-sandwich peptide-binding domain and a unique C-terminal α-helical/hook domain, the latter not found in conventional Hsp70s (PMID:14674765, PMID:24327659). In parallel it serves as a nucleotide exchange factor for the canonical ER Hsp70 BiP, catalyzing ADP→ATP exchange to release clients (PMID:16962589, PMID:25877869); in ER-associated degradation it converts ADP-BiP to ATP-BiP to disengage misfolded substrates such as NHK α1-antitrypsin and physically binds the Hrd1 adaptor Sel1L, coupling client release from BiP to retrotranslocation through the Hrd1-Sel1L complex (PMID:25877869, PMID:27030672). This dual activity makes GRP170 essential for BiP function and ER homeostasis: its loss in fibroblasts causes BiP and aggregation-prone clients to become insoluble, activates the UPR, and is lethal (PMID:38446639). Beyond quality control, GRP170 chaperones specific secretory clients, promoting VEGF secretion (PMID:11435456) and the conformational maturation and surface trafficking of the ENaC channel and the TSH receptor, with tissue-specific knockout producing renal ion-homeostasis failure and primary hypothyroidism respectively (PMID:23645669, PMID:35104250, PMID:40923318). It also regulates ER calcium homeostasis in neurons, limiting calpain/cathepsin activation and excitotoxic death (PMID:11714735). Extracellularly, GRP170's chaperoning domain mediates receptor-bound (SR-A, SREC-I) uptake by antigen-presenting cells and cross-presentation, underlying its immunoadjuvant activity (PMID:16424054, PMID:17615582).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established the existence of a previously unknown ER stress protein selectively induced by hypoxia, defining HYOU1 as an oxygen-deprivation-responsive ER component distinct from heat-shock and other stress responses.

    Evidence Protein purification, N-terminal sequencing, subcellular fractionation and nuclear run-off in astrocytes

    PMID:8617779

    Open questions at the time
    • Molecular function unknown at this stage
    • No substrate or partner identified
    • Sequence/domain identity not yet determined
  2. 1997 High

    Resolved the molecular identity of the protein by cloning the cDNA, revealing an ER-targeted HSP70-superfamily member with an ATPase-like domain and ER retention signal.

    Evidence cDNA cloning and deduced sequence/domain analysis

    PMID:9020069

    Open questions at the time
    • Chaperone activity not functionally demonstrated
    • ATPase activity not biochemically tested
    • Client proteins unknown
  3. 1999 Medium

    Demonstrated that HYOU1 is a peptide-binding ER chaperone and that its loss specifically sensitizes cells to hypoxic death, linking biochemical substrate binding to a cytoprotective function.

    Evidence TAP-mediated microsomal peptide-binding assay; stable antisense knockdown with viability/apoptosis readouts

    PMID:10037731 PMID:10441153

    Open questions at the time
    • Substrate selectivity defined only by comparison to a few ER chaperones
    • Mechanism of cytoprotection not at molecular resolution
    • ATP-dependence of binding not yet clarified
  4. 2000 High

    Identified a physiological folding client and probed ATP regulation, showing HYOU1 binds the secretory glycoprotein GP80/clusterin and binds/hydrolyzes ATP, with substrate release at low ATP.

    Evidence Co-IP, pulse-chase maturation assay, ATP-agarose binding and ATP hydrolysis assay in MDCK cells

    PMID:10837345

    Open questions at the time
    • Relationship between ATP hydrolysis and holdase activity left ambiguous
    • Single client characterized
    • No structural basis for ATP handling
  5. 2001 High

    Established HYOU1 as a physiologically protective chaperone in vivo, controlling secretion of the angiogenic client VEGF and limiting ischemic/excitotoxic neuronal death via calcium and caspase regulation.

    Evidence Transgenic/heterozygous-KO mice, adenoviral delivery, stroke and wound-healing models, calcium and calpain/cathepsin assays

    PMID:11231630 PMID:11435456 PMID:11714735

    Open questions at the time
    • Direct molecular link between HYOU1 and calcium handling not defined
    • Whether VEGF binding is direct chaperone-client engagement not shown
    • Mechanism connecting chaperone activity to caspase suppression unclear
  6. 2002 Medium

    Described a non-canonical cytoplasmic isoform lacking the signal peptide that participates in NLS-dependent nuclear import, expanding HYOU1 functions beyond the ER lumen.

    Evidence Lectin affinity purification, NLS-dependent import assay, carbohydrate epitope analysis

    PMID:11960996

    Open questions at the time
    • Mechanism of nuclear import role undefined
    • Cytoplasmic isoform abundance/relevance in vivo unclear
    • Single-lab observation
  7. 2003 High

    Reconstituted chaperone activity in vitro and mapped two substrate-binding regions, establishing HYOU1 as an ATP-independent holdase with a unique C-terminal α-helical substrate-binding feature.

    Evidence Recombinant protein, luciferase aggregation-suppression and refolding assays, domain-deletion mutagenesis

    PMID:14674765

    Open questions at the time
    • Structural basis of the α-helical domain not resolved
    • Refolding required lysate factors—co-chaperone dependence undefined
    • Physiological substrate spectrum not addressed
  8. 2006 High

    Defined a second core biochemical activity by showing HYOU1 acts as a nucleotide exchange factor for BiP, positioning it within the ER Hsp70 cycle alongside Sil1.

    Evidence Biochemical nucleotide exchange assay and functional complementation

    PMID:16962589

    Open questions at the time
    • How NEF and holdase activities are coordinated unresolved
    • In-cell consequences of NEF activity not yet demonstrated
    • No structural model of GRP170-BiP engagement
  9. 2007 High

    Explained HYOU1's immunoadjuvant property mechanistically, showing its chaperoning domain mediates receptor-dependent (SR-A, SREC-I) uptake by APCs and cross-presentation to CD8+ T cells.

    Evidence Domain-deletion mutants, saturable receptor binding on receptor-expressing cells, competitive inhibition, T-cell IFN-γ readout

    PMID:16424054 PMID:17615582

    Open questions at the time
    • Endogenous extracellular GRP170 role unclear
    • Physiological versus immunotherapeutic relevance not separated
    • Structural determinants of receptor binding undefined
  10. 2013 High

    Distinguished HYOU1 from BiP at the substrate level and defined intramolecular regulation, showing it binds only unfolded clients, remains bound in ATP, and that its α-helical domain promotes while an unstructured loop suppresses binding; also linked GRP170 holdase activity to ENaC ERAD.

    Evidence Co-IP with folded/unfolded substrates, ATP-release assay, domain-deletion mutants; yeast Lhs1 ENaC ERAD system with NEF vs holdase mutants and mammalian GRP170-αENaC Co-IP

    PMID:23645669 PMID:24327659

    Open questions at the time
    • Which clients depend on holdase vs NEF activity not generalized
    • Structural mechanism of the regulatory loop unknown
    • Selectivity for unglycosylated ENaC form mechanistically unexplained
  11. 2016 High

    Integrated NEF activity into the ERAD pathway, showing GRP170 converts ADP-BiP to ATP-BiP to release misfolded clients and binds Sel1L to couple substrate disengagement with retrotranslocation through Hrd1-Sel1L.

    Evidence siRNA/overexpression, Grp170-Sel1L Co-IP, retrotranslocation and NHK/TTR ERAD assays

    PMID:25877869 PMID:27030672

    Open questions at the time
    • Stoichiometry and spatial organization of GRP170-BiP-Sel1L not resolved
    • How holdase and NEF roles partition across glycosylated vs non-glycosylated clients unclear
    • In vivo requirement not yet established
  12. 2024 High

    Demonstrated that GRP170 is essential for BiP function and ER homeostasis at the whole-cell level, with its loss causing BiP and client insolubility, impaired client turnover, UPR activation, and death.

    Evidence Inducible conditional Grp170 knockout in MEFs, fractionation, BiP-client Co-IP, degradation and UPR/cell-death assays

    PMID:38446639

    Open questions at the time
    • Which essential clients drive lethality unresolved
    • Separation of NEF vs holdase contributions to essentiality not achieved
    • Tissue-level consequences addressed separately
  13. 2025 High

    Tied GRP170's chaperone function to tissue-specific physiology, showing it is required for ENaC-dependent renal ion homeostasis and for TSH-receptor maturation and trafficking, with knockouts causing kidney injury and primary hypothyroidism.

    Evidence Nephron- and thyrocyte-specific inducible knockout mice with in vitro trafficking/maturation assays

    PMID:35104250 PMID:40923318

    Open questions at the time
    • Direct chaperone engagement of TSHR/ENaC not shown structurally
    • Whether NEF or holdase activity is rate-limiting in vivo unclear
    • Full client repertoire across tissues unknown
  14. 2025 Medium

    Provided the first structural view of the GRP170-ATP-BiP complex, revealing a C-terminal curved hook domain and a structural basis for pseudo-ATPase chaperone activity.

    Evidence 2.7 Å cryo-EM of complex purified from HEK293 cells (preprint)

    PMID:bio_10.1101_2025.10.25.684324

    Open questions at the time
    • Preprint, not peer-reviewed
    • Hook-domain substrate engagement proposed but not functionally validated
    • Conformational dynamics of nucleotide exchange not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRP170 mechanistically partitions its holdase versus NEF activities across individual clients, and how the curved hook domain physically engages substrate during the BiP nucleotide cycle, remains unresolved.
  • No functional confirmation of the hook-domain substrate model
  • No comprehensive client repertoire mapping activity requirements
  • Coordination between substrate release and retrotranslocon engagement not structurally defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2
Partners
BACE1ENACHSPA5SEL1LTSHR

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 ORP150 (HYOU1) is a novel ~150 kDa stress protein that localizes to the endoplasmic reticulum of astrocytes, is induced de novo by hypoxia at the transcriptional level (confirmed by nuclear run-off analysis), and its expression is selective for oxygen deprivation (not induced by heat shock, hydrogen peroxide, cobalt chloride, 2-deoxyglucose, or tunicamycin in astrocytes). Protein purification (FPLC/preparative SDS-PAGE), N-terminal sequencing, antisera generation, subcellular fractionation, Northern blot, nuclear run-off analysis, cycloheximide inhibition The Journal of biological chemistry High 8617779
1997 Human ORP150 cDNA encodes a 999-residue protein containing an N-terminal signal peptide, a C-terminal ER retention-like signal, and an N-terminal half with significant similarity to the ATPase domain of HSP70 family proteins including conserved ATP-binding motifs, establishing it as a member of the HSP70 superfamily residing in the ER. cDNA cloning, deduced amino acid sequence analysis, Northern blot Biochemical and biophysical research communications High 9020069
1999 Grp170 (HYOU1) binds peptides translocated into microsomes by TAP in an ATP-independent manner, identifying it as a peptide-binding ER chaperone with substrate specificity overlapping but not identical to other ER chaperones (PDI, gp96, ERp72, calnexin). TAP-mediated peptide translocation into microsomes, peptide-binding assay, substrate specificity comparison Biochemistry Medium 10441153
1999 Suppression of ORP150 expression by stable antisense RNA transfection in HEK cells leads to reduced cell viability and accelerated apoptosis specifically under hypoxia, but not in response to oxygen-free radicals or sodium arsenate, establishing a specific cytoprotective function for ORP150 in hypoxia-induced cell death. Stable antisense RNA transfection, viability assays, apoptosis assays, caspase activity measurement, cytochrome c immunostaining The Journal of biological chemistry High 10037731
2000 ORP150 functions as a molecular chaperone in MDCK renal epithelial cells by binding to the secretory glycoprotein GP80/clusterin under hypoxia; inhibition of ORP150 causes retention of GP80 in the ER and delays its maturation. ORP150 binds ATP-agarose and hydrolyzes ATP to release substrate at lower ATP concentrations, consistent with ATP-regulated substrate release. Co-immunoprecipitation, metabolic pulse-chase labeling, affinity chromatography on ATP-agarose, ATP hydrolysis assay, stable antisense transfection American journal of physiology. Cell physiology High 10837345
2000 Human ORP150 gene produces at least three distinct mRNA species via alternative promoters; the transcript beginning with exon 1B is preferentially induced by hypoxia or tunicamycin. In vitro translation of the third mRNA (starting from exon 2, immediately upstream of AUG) generates a cytosolic form of ORP150 lacking the signal peptide due to differential translation initiation. Gene cloning and sequencing, transcription initiation site mapping, in vitro transcription/translation, Northern blot Journal of biochemistry Medium 10965054
2001 ORP150 overexpression in neurons suppresses caspase-3-like activity and enhances BDNF under hypoxia signaling; targeted neuronal overexpression in mice results in smaller infarct volumes after ischemia, while astrocytes with inhibited ORP150 expression are more vulnerable to hypoxic stress. Transgenic mouse overexpression, adenoviral gene delivery, caspase activity assay, BDNF measurement, stroke model (MCA occlusion), antisense inhibition Nature medicine High 11231630
2001 ORP150 acts as an intracellular chaperone facilitating VEGF secretion; inhibition of ORP150 in cultured human macrophages causes retention of VEGF within the ER, while ORP150 overexpression promotes VEGF secretion. Local adenoviral delivery of ORP150 to wound macrophages in diabetic mice increases VEGF levels and accelerates wound healing. Adenoviral gene delivery (sense/antisense), immunostaining for ER retention, VEGF ELISA in conditioned medium, wound healing model in diabetic mice The Journal of clinical investigation High 11435456
2001 ORP150 regulates cytosolic free calcium homeostasis in hippocampal neurons; ORP150 heterozygous-deficient mice show exaggerated cytosolic calcium elevation, enhanced mu-calpain and cathepsin B activation, and increased vulnerability to glutamate-induced cell death, while ORP150-overexpressing mice show suppression of these events. ORP150 heterozygous knockout mice, ORP150 transgenic mice, kainate model, cytosolic calcium measurement, mu-calpain and cathepsin B activity assays, in vitro glutamate toxicity The Journal of clinical investigation High 11714735
2002 A cytoplasmic N-terminally truncated form of ORP150, lacking the ER signal peptide, is a major intracellular ligand for mushroom Agaricus bisporus lectin and is required for nuclear localization sequence (NLS)-dependent nuclear protein import; this cytoplasmic form expresses the lectin carbohydrate ligand (sialyl-2,3-galactosyl-β1,3-N-acetylgalactosamine-α). Lectin affinity chromatography, immunoprecipitation, NLS-dependent import assay, carbohydrate epitope characterization The Journal of biological chemistry Medium 11960996
2003 Mouse Grp170 (HYOU1) functions as a molecular chaperone by maintaining heat-denatured luciferase in a soluble state in the absence of ATP (holdase activity), and can partially refold denatured luciferase in the presence of reticulocyte lysate. Domain deletion studies show two distinct substrate-binding regions: one homologous to the β-sandwich peptide-binding domain and a C-terminal α-helical domain, the latter being a unique substrate-binding feature not found in conventional Hsp70s. Recombinant protein expression (baculovirus), in vitro luciferase aggregation suppression assay, refolding assay, domain deletion mutagenesis Biochemistry High 14674765
2005 Grp170 (HYOU1) interacts with α1-antitrypsin Z (α1-AT Z) and other ER-retained α1-AT mutants in the ER, as demonstrated by chemical cross-linking and co-immunoprecipitation. Approximately 85% of α1-AT Z exists in soluble complexes with multiple chaperones (Grp78, Grp94, calnexin, Grp170, UDP-glucose glycoprotein:glucosyltransferase), while ~15% forms large polymers/aggregates devoid of chaperones. Chemical cross-linking, sequential immunoprecipitation/immunoblot, co-immunoprecipitation, sucrose density gradient centrifugation American journal of physiology. Gastrointestinal and liver physiology High 15845869
2006 Mammalian Grp170 acts as a nucleotide exchange factor (NEF) for BiP, catalyzing ADP release and nucleotide exchange, analogous to yeast Lhs1p. This activity likely compensates for loss of the other BiP NEF, Sil1, in cells of most tissues, explaining why SIL1 mutations (Marinesco-Sjögren syndrome) cause a non-lethal, tissue-restricted phenotype. Biochemical nucleotide exchange assay, functional complementation analysis FEBS letters High 16962589
2006 The immunoadjuvant activity of Grp170 (HYOU1) directly correlates with its chaperoning function; domain deletion mutants that lose chaperone activity also lose the ability to bind antigen-presenting cells (APCs) in a receptor-mediated manner and to stimulate antitumor immunity. Grp170 interaction with APCs is mediated by its chaperoning domain, not a separate sequence-specific receptor-binding domain. Domain deletion mutagenesis, in vitro chaperone assay, APC receptor-binding assay, antigen presentation assay, in vivo tumor immunization Cancer research Medium 16424054
2007 Grp170 (HYOU1) binds to scavenger receptor class A (SR-A) and scavenger receptor expressed by endothelial cells-I (SREC-I) on antigen-presenting cells in a saturable, receptor-mediated manner; scavenger receptor ligands inhibit this binding. SR-A and SREC-I mediate the cross-presentation of Grp170-chaperoned antigen to CD8+ T cells. Binding assay on SR-A- and SREC-I-expressing CHO cells, competitive inhibition with scavenger receptor ligands, IFN-γ ELISpot with T cells, bone marrow-derived dendritic cell binding European journal of immunology High 17615582
2007 ORP150 localizes to mitochondria in addition to the ER: the N-terminal 13 amino acids are sufficient for mitochondrial targeting, as demonstrated by GFP-fusion constructs. Mitochondrial ORP150 is upregulated by anti-CHOP/GADD153 transcription factor. ORP150 is a substrate for mitochondrial calpain 10; calcium-induced calpain 10 activity cleaves ORP150 in isolated mitochondria. Subcellular fractionation, GFP-fusion live imaging, N-terminal deletion mutagenesis, Western blot (mitochondrial fractions), calpain inhibitor experiments, in vitro cleavage assay American journal of physiology. Cell physiology Medium 18094145
2013 Grp170 (HYOU1) directly binds incompletely folded (unfolded) protein substrates in the ER but not folded secretory proteins. Unlike BiP (conventional Hsp70), Grp170 remains bound to substrates in the presence of ATP. The extended C-terminal α-helical domain is required for full substrate binding (deletion reduces interaction), while the unstructured loop in the putative substrate-binding domain suppresses binding (deletion increases interaction), revealing unique intramolecular regulation of large Hsp70 chaperone activity. Co-immunoprecipitation with unfolded vs. folded substrates, ATP-release assay, domain deletion mutagenesis (α-helical domain, unstructured loop), comparative analysis with BiP The Journal of biological chemistry High 24327659
2013 The yeast Lhs1/GRP170 ortholog facilitates ERAD of the ENaC α-subunit; the nucleotide exchange (NEF) activity of Lhs1 is dispensable for this function, but its holdase/chaperone activity is required. The mammalian homolog GRP170 co-precipitates with αENaC and facilitates ENaC degradation in HEK293 cells and Xenopus oocytes, selectively affecting the unglycosylated form of the protein. Yeast ENaC expression system, ATP-binding mutants of Lhs1, Co-immunoprecipitation (Lhs1-αENaC; GRP170-αENaC), degradation assay in HEK293 and Xenopus oocytes, glycosylation analysis The Journal of biological chemistry High 23645669
2015 Grp170 (HYOU1) triggers nucleotide exchange on BiP (ADP→ATP), causing ATP-BiP to disengage from misfolded ERAD substrate NHK (null Hong Kong α1-antitrypsin), enabling NHK retrotranslocation to the cytosol. Grp170 physically binds to Sel1L (adapter of the Hrd1 E3 ubiquitin ligase/retrotranslocon), linking client release from BiP to retrotranslocation. Grp170 also promotes degradation of the non-glycosylated misfolded client TTR D18G. Loss- and gain-of-function approaches (siRNA/overexpression), co-immunoprecipitation (Grp170-Sel1L), retrotranslocation assay, cholera toxin (NHK) ERAD assay Molecular biology of the cell High 25877869
2016 Grp170 (HYOU1) acts as a NEF for BiP to drive ERAD of the misfolded glycosylated client NHK: Grp170 converts ADP-BiP to ATP-BiP, releasing NHK to allow retrotranslocation through the Hrd1-Sel1L complex. Grp170 directly binds Sel1L, positioning client release at the retrotranslocation site to couple substrate disengagement from BiP with retrotranslocation. Knockdown and overexpression studies, binding assays (Grp170-Sel1L interaction), ERAD functional assay, NHK retrotranslocation assay Molecular biology of the cell High 27030672
2018 AMPK activation induces ORP150 expression via the transcription factor FOXO1; lentiviral shRNA silencing of AMPK or FOXO1 reduces ORP150 levels and increases CHOP expression and ER stress-induced apoptosis in bronchial epithelial cells. FOXO1 is identified as a transcriptional regulator of ORP150. Pharmacological AMPK activation (AICAR), lentiviral shRNA knockdown of AMPK and FOXO1, Western blot, Annexin V-PI flow cytometry apoptosis assay Biochemical and biophysical research communications Medium 29448096
2018 ORP150 (HYOU1) physically interacts with and stabilizes BACE1 at the post-translational level; ORP150 promotes BACE1-mediated amyloid (Aβ42) processing and prevents CHIP-mediated BACE1 ubiquitin-dependent degradation. ORP150 and CHIP show mutual antagonism, inversely regulating each other under normal and stress conditions. Co-immunoprecipitation (ORP150-BACE1), siRNA knockdown, overexpression, Western blot for BACE1/Aβ42 levels, CHIP ubiquitination assay Journal of cellular biochemistry Medium 29266373
2021 Inhibition of HYOU1 expression in lung cancer multicellular tumor spheroids suppresses stemness and malignancy, facilitates apoptosis, and increases chemosensitivity. Mechanistically, HYOU1 inhibition decreases activity of the PI3K/AKT/mTOR pathway, placing HYOU1 upstream of PI3K/AKT/mTOR signaling in lung cancer cells. siRNA knockdown, multicellular tumor spheroid model, apoptosis assays, Western blot for PI3K/AKT/mTOR pathway components, chemosensitivity assay Molecules and cells Medium 33455947
2021 HYOU1 silencing in papillary thyroid cancer cells promotes oxidative phosphorylation while inhibiting aerobic glycolysis by downregulating LDHB at the posttranscriptional level via increased miR-375-3p. LDHB mRNA 3'UTR is the indirect target of HYOU1 action; LDHB overexpression rescues the metabolic and pro-tumorigenic effects of HYOU1 knockdown. siRNA knockdown, Western blot, qRT-PCR, metabolic assays, miR-375-3p measurement, LDHB overexpression rescue experiment, proliferation/migration/invasion assays Journal of cellular and molecular medicine Medium 33792181
2022 Nephron-specific GRP170 (HYOU1) knockout mice develop profound hypovolemia, hyperaldosteronemia, ion homeostasis dysregulation associated with loss of ENaC, and hallmarks of acute kidney injury with activation of the unfolded protein response (UPR), establishing GRP170 as an essential chaperone for kidney ENaC function and renal homeostasis. Inducible nephron-specific Cre/LoxP knockout mouse, electrolyte and kidney function measurements, ENaC Western blot, UPR marker analysis JCI insight High 35104250
2023 FUT2-mediated α-1,2-fucosylation of HYOU1 at the N-glycosylation site asparagine (Asn) 862 facilitates intestinal stem cell survival, self-renewal, and resistance to ER stress and inflammatory injury. FUT2 depletion in ISCs escalates LPS-induced ER stress via the IRE1/TRAF2/ASK1/JNK UPR branch; fucosylation of HYOU1 at Asn862 is the mediating modification. N-glycoproteomics, UEA-1 lectin chromatography, site-directed mutagenesis (Asn862), intestinal organoid assays, ISC-specific Fut2 knockout mice, flow cytometry, Western blot Redox biology High 36724577
2023 METTL3-mediated m6A methylation of HYOU1 mRNA, read by IGF2BP3, increases HYOU1 mRNA stability and protein expression, conferring doxorubicin resistance in breast cancer cells. Knockdown of METTL3 or HYOU1 overcomes doxorubicin resistance. RIP assay, MeRIP assay, dual-luciferase reporter assay, siRNA knockdown, CCK-8 viability, Annexin V flow cytometry, Western blot, qRT-PCR Biochimica et biophysica acta. General subjects Medium 38103759
2024 Loss of Grp170 (HYOU1) in mouse embryonic fibroblasts causes BiP to fractionate with insoluble material, increases steady-state BiP binding to clients with reduced client turnover, reduces solubility of aggregation-prone BiP substrates, and induces UPR activation, culminating in cell death. These effects establish that Grp170 is essential for BiP function and ER homeostasis. Conditional Cre/LoxP Grp170 knockout in MEFs (doxycycline-inducible), subcellular fractionation, co-immunoprecipitation (BiP-client), client degradation assay, UPR marker Western blot, cell death assay Molecular biology of the cell High 38446639
2025 Thyrocyte-specific loss of GRP170 (HYOU1) causes primary hypothyroidism with deficient TSH responsiveness. In cultured PCCL3 thyrocytes, GRP170 knockdown inhibits folding and forward trafficking of TSH receptors to the cell surface, establishing GRP170 as required for TSH receptor conformational maturation and thyroid hormone synthesis. Inducible Pax8-Cre thyroid-specific GRP170 knockout mice, siRNA knockdown in PCCL3 thyrocytes, TSH receptor surface trafficking assay, thyroid hormone measurements JCI insight High 40923318
2025 Cryo-EM structure at 2.7 Å of the GRP170-ATP-BiP complex reveals a C-terminal curved hook domain in GRP170 that is proposed to engage substrate in coordination with BiP. The structure also reveals the structural basis for GRP170 pseudo-ATPase chaperone activity, making it the first chaperone of this type. The complex was purified from HEK293 cells. Cryo-electron microscopy (2.7 Å), protein complex purification from HEK293 cells bioRxivpreprint Medium bio_10.1101_2025.10.25.684324
2016 In thyroid cancer cells, ORP150 (HYOU1) transcription is induced by proteasome inhibition through two mechanisms: (1) Nrf2 directly binds and transactivates the −421/−307 region of the ORP150 promoter; (2) Nrf2 indirectly activates ORP150 via facilitating ATF4 recruitment to the −243/+53 region. Activating transcription factor 4 (ATF4) is required for ORP150 induction (siATF4 inhibits upregulation). Promoter deletion analysis, ChIP/reporter assay, siRNA knockdown of Nrf2 and ATF4, Western blot, real-time RT-PCR Oncotarget Medium 26700459
2025 CPE stabilizes HYOU1 protein by inhibiting ubiquitin-proteasome degradation; CPE deficiency causes reduced HYOU1 protein levels. In osteosarcoma cells, CPE activates Hippo-YAP signaling and promotes YAP nuclear translocation. Overexpression of HYOU1 rescues the anti-tumor and pro-PANoptosis effects of CPE knockdown, placing HYOU1 downstream of CPE in this pathway. CPE knockdown/knockout, HYOU1 overexpression rescue, proteasome inhibitor treatment, Western blot for ubiquitination and YAP pathway, xenograft tumor model, immunofluorescence for YAP localization Cancer letters Low 41213463

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 ORP150 protects against hypoxia/ischemia-induced neuronal death. Nature medicine 171 11231630
1996 Purification and characterization of a novel stress protein, the 150-kDa oxygen-regulated protein (ORP150), from cultured rat astrocytes and its expression in ischemic mouse brain. The Journal of biological chemistry 171 8617779
2015 BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions. Journal of molecular biology 160 25698114
1999 150-kDa oxygen-regulated protein (ORP150) suppresses hypoxia-induced apoptotic cell death. The Journal of biological chemistry 152 10037731
2001 Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. The Journal of clinical investigation 124 11435456
2001 Expression of the endoplasmic reticulum molecular chaperone (ORP150) rescues hippocampal neurons from glutamate toxicity. The Journal of clinical investigation 121 11714735
2005 Grp78, Grp94, and Grp170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum. American journal of physiology. Gastrointestinal and liver physiology 86 15845869
1997 Cloning and expression of cDNA encoding the human 150 kDa oxygen-regulated protein, ORP150. Biochemical and biophysical research communications 86 9020069
2004 ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 74 15240565
2007 Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor-A and scavenger receptor expressed by endothelial cells-I. European journal of immunology 65 17615582
2004 ORP150/HSP12A regulates Purkinje cell survival: a role for endoplasmic reticulum stress in cerebellar development. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 14960622
2003 The chaperoning properties of mouse grp170, a member of the third family of hsp70 related proteins. Biochemistry 63 14674765
2006 The nucleotide exchange factor activity of Grp170 may explain the non-lethal phenotype of loss of Sil1 function in man and mouse. FEBS letters 61 16962589
1999 Identification of novel peptide binding proteins in the endoplasmic reticulum: ERp72, calnexin, and grp170. Biochemistry 56 10441153
2013 The large Hsp70 Grp170 binds to unfolded protein substrates in vivo with a regulation distinct from conventional Hsp70s. The Journal of biological chemistry 50 24327659
2006 Chaperoning function of stress protein grp170, a member of the hsp70 superfamily, is responsible for its immunoadjuvant activity. Cancer research 50 16424054
2007 HYOU1/Orp150 expression in breast cancer. Medical science monitor : international medical journal of experimental and clinical research 49 17968289
2015 GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: nucleotide exchange factors for Hsp70 molecular chaperones. Sub-cellular biochemistry 48 25487014
2013 The Lhs1/GRP170 chaperones facilitate the endoplasmic reticulum-associated degradation of the epithelial sodium channel. The Journal of biological chemistry 48 23645669
2008 Secretable chaperone Grp170 enhances therapeutic activity of a novel tumor suppressor, mda-7/IL-24. Cancer research 48 18483274
2003 Immunization with tumor-derived ER chaperone grp170 elicits tumor-specific CD8+ T-cell responses and reduces pulmonary metastatic disease. International journal of cancer 48 12673684
2021 Circular RNA 0025984 Ameliorates Ischemic Stroke Injury and Protects Astrocytes Through miR-143-3p/TET1/ORP150 Pathway. Molecular neurobiology 47 34435328
2021 Biological Function of HYOU1 in Tumors and Other Diseases. OncoTargets and therapy 45 33707955
2000 150-kDa oxygen-regulated protein (ORP150) functions as a novel molecular chaperone in MDCK cells. American journal of physiology. Cell physiology 44 10837345
2023 FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response. Redox biology 42 36724577
2020 Endogenous metabolite, kynurenic acid, attenuates nonalcoholic fatty liver disease via AMPK/autophagy- and AMPK/ORP150-mediated signaling. Journal of cellular physiology 42 33283879
2018 AMPK alleviates endoplasmic reticulum stress by inducing the ER-chaperone ORP150 via FOXO1 to protect human bronchial cells from apoptosis. Biochemical and biophysical research communications 37 29448096
2013 CHOP/ORP150 ratio in endoplasmic reticulum stress: a new mechanism for diabetic peripheral neuropathy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 36 23988440
2018 Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression. The Journal of pharmacology and experimental therapeutics 35 29572342
2013 Molecular chaperone ORP150 in ER stress-related diseases. Current pharmaceutical design 35 23363441
2004 ORP150 ameliorates ischemia/reperfusion injury from middle cerebral artery occlusion in mouse brain. Brain research 35 15223375
2008 Expression of oxygen-regulated protein 150 (ORP150) in skin wound healing and its application for wound age determination. International journal of legal medicine 34 18563428
2007 Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress. American journal of physiology. Cell physiology 34 18094145
2021 HYOU1 facilitates proliferation, invasion and glycolysis of papillary thyroid cancer via stabilizing LDHB mRNA. Journal of cellular and molecular medicine 30 33792181
2000 Production of three distinct mRNAs of 150 kDa oxygen-regulated protein (ORP150) by alternative promoters: preferential induction of one species under stress conditions. Journal of biochemistry 30 10965054
2015 The Endoplasmic Reticulum Chaperone GRP170: From Immunobiology to Cancer Therapeutics. Frontiers in oncology 29 25629003
2016 The Grp170 nucleotide exchange factor executes a key role during ERAD of cellular misfolded clients. Molecular biology of the cell 28 27030672
2001 Apoptosis and expression of stress protein (ORP150, HO1) during development of ischaemic osteonecrosis in the rat. The Journal of bone and joint surgery. British volume 28 11476318
2002 An N-terminal truncated form of Orp150 is a cytoplasmic ligand for the anti-proliferative mushroom Agaricus bisporus lectin and is required for nuclear localization sequence-dependent nuclear protein import. The Journal of biological chemistry 26 11960996
2002 Polymorphisms in the oxygen-regulated protein 150 gene (ORP150) are associated with insulin resistance in Pima Indians. Diabetes 24 11978664
2006 Immunoadjuvant chaperone, GRP170, induces 'danger signals' upon interaction with dendritic cells. Immunology and cell biology 23 16519738
2022 The molecular chaperone GRP170 protects against ER stress and acute kidney injury in mice. JCI insight 22 35104250
2021 The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer. Cells 22 33525518
2015 The nucleotide exchange factors Grp170 and Sil1 induce cholera toxin release from BiP to enable retrotranslocation. Molecular biology of the cell 22 25877869
2021 Expression of HYOU1 via Reciprocal Crosstalk between NSCLC Cells and HUVECs Control Cancer Progression and Chemoresistance in Tumor Spheroids. Molecules and cells 21 33455947
2009 Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor. Cancer immunology, immunotherapy : CII 20 19142636
2006 Increased stress protein ORP150 autoantibody production in Type 1 diabetic patients. Diabetic medicine : a journal of the British Diabetic Association 18 16433723
2006 Endoplasmic reticulum retention signal-dependent glycylation of the Hsp70/Grp170-related Pgp1p in Tetrahymena. Eukaryotic cell 18 17189490
2010 Implication of oxygen-regulated protein 150 (ORP150) in apoptosis induced by proteasome inhibitors in human thyroid cancer cells. The Journal of clinical endocrinology and metabolism 17 20719828
2023 Nucleotide Exchange Factors for Hsp70 Molecular Chaperones: GrpE, Hsp110/Grp170, HspBP1/Sil1, and BAG Domain Proteins. Sub-cellular biochemistry 16 36520302
2016 Hypoxia mediates osteocyte ORP150 expression and cell death in vitro. Molecular medicine reports 16 27748851
2022 HYOU1 promotes cell proliferation, migration, and invasion via the PI3K/AKT/FOXO1 feedback loop in bladder cancer. Molecular biology reports 15 36348197
2021 Long non-coding RNA KCNQ1OT1 facilitates the progression of cervical cancer and tumor growth through modulating miR-296-5p/HYOU1 axis. Bioengineered 14 34704918
2021 Long non-coding antisense RNA HYOU1-AS is essential to human breast cancer development through competitive binding hnRNPA1 to promote HYOU1 expression. Biochimica et biophysica acta. Molecular cell research 13 33422616
2023 METTL3/IGF2BP3-regulated m6A modification of HYOU1 confers doxorubicin resistance in breast cancer. Biochimica et biophysica acta. General subjects 12 38103759
2013 Low-glucose medium induces ORP150 expression and exerts inhibitory effect on apoptosis and senescence of human breast MCF7 cells. Acta biochimica Polonica 12 23757447
2010 Tumour secreted grp170 chaperones full-length protein substrates and induces an adaptive anti-tumour immune response in vivo. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 12 20210603
2010 Vaccination with a chaperone complex based on PSCA and GRP170 adjuvant enhances the CTL response and inhibits the tumor growth in mice. Vaccine 12 20637304
2004 The expression of '150-kDa oxygen regulated protein (ORP-150)' in human brain and its relationship with duration time until death. Legal medicine (Tokyo, Japan) 12 15039052
2024 Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum function. Molecular biology of the cell 11 38446639
2019 The 150-kDa oxygen-regulated protein (ORP150) regulates proteinuria in diabetic nephropathy via mediating VEGF. Experimental and molecular pathology 11 31028725
2013 Lysophosphatidic acid promotes secretion of VEGF by increasing expression of 150-kD Oxygen-regulated protein (ORP150) in mesenchymal stem cells. Biochimica et biophysica acta 11 23707263
2010 The timing of perinatal hypoxia/ischemia events in term neonates: a retrospective autopsy study. HSPs, ORP-150 and COX2 are reliable markers to classify acute, perinatal events. Diagnostic pathology 11 20626887
2011 Effects of ORP150 on appearance and function of pancreatic beta cells following acute necrotizing pancreatitis. Pathology, research and practice 10 21536389
2003 Enforced expression of oxygen-regulated protein, ORP150, induces vacuolar degeneration in mouse myocardium. Transgenic research 10 12650521
2018 Understanding the role of glucose regulated protein 170 (GRP170) as a nucleotide exchange factor through molecular simulations. Journal of molecular graphics & modelling 8 30205291
2016 Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells. Oncotarget 8 26700459
2012 Expression of 150-kDa oxygen-regulated protein (ORP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice. Biochemical and biophysical research communications 8 22892132
2002 The increment of anti-ORP150 autoantibody in initial stages of atheroma in high-fat diet fed mice. The Journal of veterinary medical science 8 11913559
2022 Abietic acid alleviates endoplasmic reticulum stress and lipid accumulation in human primary hepatocytes through the AMPK/ORP150 signaling. Biochemical and biophysical research communications 7 35398611
2024 Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation. Angewandte Chemie (International ed. in English) 6 38339863
2024 Excess dietary sodium restores electrolyte and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron. American journal of physiology. Renal physiology 6 39556479
2018 ORP150-CHIP chaperone antagonism control BACE1-mediated amyloid processing. Journal of cellular biochemistry 6 29266373
2008 Vacuolar degeneration of skeletal muscle in transgenic mice overexpressing ORP150. The Journal of veterinary medical science 6 18250584
2022 Red Algae “Sarcodia suieae” Acetyl-Xylogalactan Downregulate Heat-Induced Macrophage Stress Factors Ddit3 and Hyou1 Compared to the Aquatic Animal Model of Nile Tilapia (Oreochromis niloticus) Brain Arachidonic Acid Expression. International journal of molecular sciences 4 36498988
2013 Engineering Grp170-based immune modulators for cancer immunotherapy. Oncoimmunology 3 23894699
2007 Abetalipoproteinemia induced by overexpression of ORP150 in mice. Comparative medicine 3 17605339
2003 [ORP150 (150 kDa oxygen regulated protein) suppressed neuronal cell death]. Nihon yakurigaku zasshi. Folia pharmacologica Japonica 3 12617037
2025 Thyroidal expression of ER molecular chaperone GRP170 is required for efficient TSH-mediated thyroid hormone synthesis. JCI insight 2 40923318
2023 Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum functions. bioRxiv : the preprint server for biology 2 37905119
2025 CPE/HYOU1 axis-activated Hippo-YAP signaling pathway suppresses PANoptosis to facilitate osteosarcoma progression. Cancer letters 1 41213463
2024 Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron. bioRxiv : the preprint server for biology 1 38260467
2025 Endoplasmic reticulum stress upregulate HYOU1 and mediates lenvatinib resistance in liver cancer through ERK/MAPK pathway. Frontiers of medicine 0 41405831
2025 A Unique Pathogenic Heterozygous Hypoxia Up-Regulated Protein 1 (HYOU1) Mutation Presenting With Recurrent Osteomyelitis, Subglottic Stenosis, and Hypoglycemia. Cureus 0 41583281
2024 Overexpression of HYOU1 is associated with cisplatin resistance and may depend on m6A modification in patients with cervical cancer. Oncology letters 0 39650230
2022 The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects. Iranian journal of allergy, asthma, and immunology 0 35822684

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