Affinage

HERPUD1

Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein · UniProt Q15011

Length
391 aa
Mass
43.7 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HERPUD1 (Herp) is an ER-resident integral membrane protein that serves as a central scaffold in the HRD1-dependent ERAD pathway, coupling substrate recognition to retrotranslocation and proteasomal degradation of misfolded ER proteins. Its N-terminal ubiquitin-like (UBL) domain is essential for direct binding to the E3 ligase HRD1, recruitment of DERL2, p97, and ubiquilin shuttle factors to the retrotranslocation complex, and for efficient substrate ubiquitination; Herp localizes to the ER quality control compartment and is required for HRD1 compartmentalization there (PMID:16289116, PMID:24366871, PMID:24478453, PMID:21149444). Beyond general ERAD, HERPUD1 regulates ER calcium homeostasis by promoting UBL-dependent proteasomal degradation of IP3 receptors and ryanodine receptors, thereby limiting ER-to-mitochondria Ca²⁺ transfer and protecting against stress-induced apoptosis and pathological cardiac hypertrophy (PMID:22045699, PMID:26616647, PMID:29042597). HERPUD1 itself is a short-lived protein whose transcription is induced through all three UPR branches (IRE1/XBP1, ATF6, PERK/ATF4) and additional factors (Luman/CREB3, Nrf1), while its turnover is controlled by gp78/Ube2g2-mediated ubiquitination via its UBL domain and by POSH-mediated K63-linked ubiquitination that directs its relocalization from the trans-Golgi network to the ER during calcium stress (PMID:14742429, PMID:24496447, PMID:17420289).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Identification of HERPUD1 as a novel ER-resident, UBL-domain-containing membrane protein strongly induced by ER stress established it as a UPR target gene and predicted a role in ER protein quality control.

    Evidence Immunochemistry, membrane topology determination, mRNA/protein induction assays in mammalian cells; promoter ERSE reporter assays

    PMID:10708769 PMID:10922362

    Open questions at the time
    • No interacting partners or substrates identified
    • Function of the UBL domain unknown
    • ER stress induction pathway branches not resolved
  2. 2002 High

    The discovery that HERPUD1 physically interacts with presenilins and enhances gamma-secretase-mediated Aβ generation revealed an unexpected link between ER quality control and amyloid processing.

    Evidence Co-immunoprecipitation and cell-based Aβ generation assays in PS-null and wild-type cells

    PMID:11799129

    Open questions at the time
    • Whether presenilin interaction is direct or bridged by other ERAD components unclear
    • Physiological relevance of Aβ modulation in vivo not tested
  3. 2003 Medium

    Dissection of the UBL domain showed it is required for rapid proteasomal turnover of HERPUD1 itself but dispensable for presenilin binding, separating the self-degradation signal from the protein interaction surface.

    Evidence UBL deletion mutagenesis with pulse-chase degradation and Aβ assays

    PMID:14550564

    Open questions at the time
    • E3 ligase mediating UBL-dependent degradation not identified
    • UBL domain binding partners beyond presenilin unknown
  4. 2004 High

    Three concurrent advances defined HERPUD1's functional roles: all three UPR branches (IRE1/XBP1, ATF6, PERK/ATF4) converge on its transcriptional induction; knockout cells confirmed it is required for ERAD substrate degradation and cell survival under ER stress; and it was shown to stabilize ER Ca²⁺ homeostasis and protect neurons from ER stress-induced apoptosis.

    Evidence Branch-specific UPR activators and ATF4-KO cells for transcription; F9 Herp-null cells with ERAD substrate assays and ULD rescue; siRNA/overexpression with Ca²⁺ imaging and caspase mutagenesis in neurons

    PMID:14742429 PMID:15102845 PMID:15147274

    Open questions at the time
    • Molecular partners in the ERAD complex not yet identified
    • Mechanism of Ca²⁺ regulation unknown — target Ca²⁺ channels not identified
    • Whether caspase cleavage is a regulatory switch or bystander effect unclear
  5. 2005 High

    Biochemical characterization of the HRD1 retrotranslocation complex revealed HERPUD1 as a direct HRD1-binding scaffold that co-assembles with p97, Derlin-1, and VIMP, placing it at the core of the ERAD retrotranslocon.

    Evidence Co-immunoprecipitation and pulldown assays defining complex architecture

    PMID:16289116

    Open questions at the time
    • Stoichiometry and structural arrangement of the complex unknown
    • Whether HERPUD1 recruits components or is recruited itself unclear
  6. 2006 High

    Identification of Luman/CREB3 as a transcription factor that directly binds ERSE-II in the HERPUD1 promoter added a fourth transcriptional regulator and defined the specific cis-element mediating ER stress-induced expression.

    Evidence ChIP, promoter mutagenesis, siRNA knockdown, reporter assays

    PMID:16940180

    Open questions at the time
    • Relative contribution of Luman vs. ATF6/XBP1/ATF4 to Herp induction under different stress types not quantified
  7. 2007 High

    Two key findings refined HERPUD1's mechanism: it functions specifically in ERAD of nonglycosylated BiP substrates (not calnexin substrates), demonstrating substrate-pathway specificity; and POSH-mediated K63-linked ubiquitination regulates its relocalization from the trans-Golgi network to the ER upon calcium perturbation.

    Evidence siRNA depletion with substrate-specific ERAD assays and Co-IP; confocal microscopy with dominant-negative POSH, in vitro ubiquitination, and Ca²⁺ imaging

    PMID:17420289 PMID:18042451

    Open questions at the time
    • trans-Golgi localization under basal conditions conflicts with ER localization reported by others; resolution unclear
    • Whether K63-ubiquitination directly drives ER targeting or signals through adaptors unknown
  8. 2008 Medium

    HERPUD1's interaction with ubiquilin shuttle factors linked its scaffold function to delivery of ubiquitinated ERAD substrates to the proteasome, extending the mechanistic model beyond retrotranslocation.

    Evidence Co-immunoprecipitation, siRNA knockdown, ERAD substrate (CD3δ) stability assays with deletion mutagenesis

    PMID:18307982

    Open questions at the time
    • Direct vs. indirect interaction with ubiquilins not distinguished
    • Whether ubiquilin binding is UBL-dependent not determined
  9. 2010 High

    Multiple studies resolved how HERPUD1 is degraded and how it regulates HRD1 activity: the UBL domain is required for HRD1-dependent ubiquitylation of substrates, multiple Herp molecules can bind a single HRD1 complex, and PRKCSH antagonizes Herp-mediated ubiquitination of polycystin-2/TRPP2.

    Evidence UBL mutagenesis with ubiquitylation and pulse-chase assays; Co-IP defining Herp-PRKCSH interaction and TRPP2 ubiquitination in zebrafish and mammalian cells

    PMID:19801576 PMID:21149444

    Open questions at the time
    • Structural basis for UBL domain's activation of HRD1 catalytic activity unknown
    • Whether PRKCSH-Herp competition is a general ERAD regulatory mechanism unclear
  10. 2011 High

    Identification of IP3 receptors and ryanodine receptors as HERPUD1-dependent ERAD substrates provided the molecular mechanism for its calcium-regulatory function: UBL-dependent proteasomal degradation of these channels controls ER Ca²⁺ store size.

    Evidence siRNA knockdown, UBL deletion mutagenesis, proteasome inhibition, Ca²⁺ imaging, Western blot for IP3R/RyR levels

    PMID:22045699

    Open questions at the time
    • Whether Herp directly ubiquitinates IP3R/RyR or acts through HRD1 not distinguished
    • Selectivity for specific IP3R/RyR isoforms not determined
  11. 2012 High

    Herp-knockout mice confirmed in vivo roles in ERAD (hepatic substrate accumulation), glucose metabolism, and brain ischemia vulnerability, validating the cell-based mechanistic findings at the organismal level.

    Evidence Gene-targeted Herp-KO mice with glucose tolerance testing, brain ischemia model, and hepatic ERAD substrate assays

    PMID:22479592

    Open questions at the time
    • Specific ERAD substrates driving glucose intolerance not identified
    • Contribution of calcium dysregulation vs. ERAD failure to ischemia vulnerability not resolved
  12. 2013 High

    HERPUD1 and its homolog HERPUD2 were shown to cooperatively recruit DERL2 to the HRD1-SEL1L complex and facilitate substrate retrotranslocation, while Herp depletion was found to upregulate Beclin-1 and enhance autophagy — revealing crosstalk between ERAD and autophagy.

    Evidence Double siRNA depletion with Co-IP of ERAD complex components and substrate ubiquitination/retrotranslocation assays; stable Herp KD with autophagy flux assays and Beclin-1 protein stability measurement

    PMID:24120520 PMID:24366871

    Open questions at the time
    • Whether HERPUD1 and HERPUD2 are functionally redundant or have distinct substrate preferences unknown
    • Whether autophagy upregulation upon Herp loss is compensatory or pathological unclear
  13. 2014 High

    Two studies clarified HERPUD1's spatial regulation and turnover: it localizes to the ERQC compartment where it recruits HRD1 via a PERK-dependent mechanism, and its own degradation during stress recovery is mediated by the gp78/Ube2g2 E2-E3 pair recognizing its UBL domain through gp78's CUE domain.

    Evidence Fluorescence microscopy of ERQC localization with siRNA; in vitro ubiquitylation reconstitution with CUE-UBL domain interaction mapping and protein stability assays

    PMID:24478453 PMID:24496447

    Open questions at the time
    • How gp78 and HRD1 compete for Herp UBL binding not resolved
    • ERQC compartment identity and Herp's role in its biogenesis not fully defined
  14. 2015 High

    Nrf1 was identified as an additional transcriptional regulator of HERPUD1 through direct binding to AREs in its promoter, while functional studies confirmed that HERPUD1-mediated IP3R degradation limits ER-to-mitochondria Ca²⁺ transfer to protect against oxidative stress-induced apoptosis.

    Evidence Nrf1-KO cells with ChIP and promoter assays; stable HERPUD1 KD with cytosolic/mitochondrial Ca²⁺ imaging and pharmacological IP3R antagonist rescue

    PMID:25637874 PMID:26616647

    Open questions at the time
    • Relative contribution of Nrf1 vs. UPR transcription factors to basal vs. stress-induced expression not quantified
    • Whether mitochondrial Ca²⁺ overload is the sole apoptotic mechanism downstream of Herp loss unclear
  15. 2017 High

    In vivo cardiac phenotyping showed Herpud1-KO mice develop pathological cardiac hypertrophy due to IP3R1 accumulation and Ca²⁺ overload, while a separate study revealed HERPUD1 participates in antiviral innate immunity by binding TBK1 to amplify MAVS-IRF3-NF-κB interferon signaling.

    Evidence Herpud1-KO mice with cardiac phenotyping, siRNA in cardiomyocytes with IP3R and Ca²⁺ readouts; Co-IP of HERP-TBK1, KD/OE with IRF3/NF-κB phosphorylation, IFN reporter, and viral replication assays

    PMID:28954889 PMID:29042597

    Open questions at the time
    • Whether TBK1 interaction depends on UBL domain or transmembrane region not determined
    • Mechanism linking ERAD scaffold function to innate immune signaling unclear
    • Whether cardiac hypertrophy phenotype is fully explained by IP3R1 accumulation not resolved
  16. 2018 Medium

    HERPUD1 was found to be required for osteoblast differentiation and mineralization, expanding its physiological roles beyond ER stress to developmental cell fate decisions.

    Evidence HERPUD1 KD and OE in MC3T3-E1 and primary osteoblasts with differentiation marker and mineralization assays

    PMID:29570393

    Open questions at the time
    • Which ERAD substrates or Ca²⁺ targets mediate the osteoblast differentiation effect unknown
    • In vivo bone phenotype of Herp-KO mice not reported
  17. 2021 Medium

    Placement of HERPUD1 downstream of the p300/XBP1s axis in hypoxic macrophages showed it promotes M2 polarization and choroidal neovascularization, linking its UPR-dependent expression to immunometabolic reprogramming.

    Evidence Co-IP of p300-XBP1s, acetylation assays, siRNA in macrophages, in vivo laser-induced CNV model

    PMID:34057287

    Open questions at the time
    • Direct mechanism by which HERPUD1 protein drives M2 polarization not defined
    • Whether ERAD activity or Ca²⁺ regulation mediates the macrophage phenotype unknown
  18. 2022 Medium

    A study in liver cancer linked HERPUD1 to ferroptosis regulation through an MDM2-GSS-GSH axis: HERPUD1 reduces MDM2 ubiquitination, enabling MDM2-mediated GSS degradation, which depletes glutathione and sensitizes cells to ferroptosis.

    Evidence siRNA/OE with ubiquitination assays for MDM2 and GSS, GSH measurement, xenograft mouse model

    PMID:36038536

    Open questions at the time
    • Mechanism by which HERPUD1 reduces MDM2 ubiquitination (direct deubiquitination vs. competition) not determined
    • Whether this pathway operates outside liver cancer cells unknown
    • Relationship to HERPUD1's established ERAD/HRD1 functions unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for HERPUD1's scaffold function within the HRD1 retrotranslocon, how its ERAD and Ca²⁺-regulatory activities are coordinated in different tissues, and whether its roles in innate immunity, ferroptosis, and macrophage polarization reflect a unified mechanism or context-specific moonlighting.
  • No high-resolution structure of HERPUD1 or its complex with HRD1
  • Tissue-specific substrate repertoire not systematically defined
  • Mechanistic basis for non-ERAD functions (TBK1 interaction, MDM2 regulation, M2 polarization) not unified with core ERAD scaffold role

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
AMFRDERL1DERL2HRD1PSEN1TBK1UBQLN1VCP
Complex memberships
HRD1-Derlin-1-p97-VIMP retrotransloconHRD1-SEL1L ERAD complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 HERPUD1 (Herp) is an ER-resident integral membrane protein with a ubiquitin-like domain at the N-terminus, with both N and C termini facing the cytoplasmic side of the ER membrane. It is strongly induced by ER stress (homocysteine, tunicamycin, thapsigargin, A23187, mercaptoethanol) and is a 54-kDa membrane-associated protein. Immunochemical analysis, membrane topology determination, mRNA/protein induction assays The Journal of biological chemistry High 10922362
2000 HERPUD1 mRNA is induced by ER stress via an ER stress-responsive element (ERSE) in its 5' flanking region, placing it as a UPR target gene. Reporter assay with ERSE element from Mif1/HERPUD1 promoter, mRNA induction by tunicamycin FEBS letters Medium 10708769
2002 HERPUD1 (Herp) interacts physically with presenilin 1 (PS1) and presenilin 2 (PS2) and enhances presenilin-mediated gamma-cleavage to increase amyloid beta-protein (Abeta) generation; this effect requires presenilin (not observed in PS-deficient cells). Co-immunoprecipitation, cell-based Abeta generation assays in PS-deficient cells The Journal of biological chemistry High 11799129
2003 The ubiquitin-like domain (ULD) of HERPUD1 is required for its rapid proteasome-mediated degradation but is not essential for its interaction with presenilin or for enhancement of Abeta generation. ULD deletion mutagenesis, Abeta generation assays, pulse-chase degradation assays FEBS letters Medium 14550564
2004 HERPUD1 (Herp) is dually regulated during the unfolded protein response: both the ER stress-specific branches (IRE1/XBP-1 and ATF6-dependent) and the shared branch (PERK/eIF-2alpha phosphorylation-dependent via ATF4) contribute to its induction. ATF4 is required for Herp induction when only the shared branch is activated, but is not strictly required when both branches are active. Genetic dissection using branch-specific UPR activators and ATF4 knockout cells, mRNA/protein induction assays The Journal of biological chemistry High 14742429
2004 HERPUD1 (Herp) is itself rapidly degraded by the proteasome, and is an ERAD substrate. In F9 Herp-null cells, an endogenous ERAD substrate is stabilized and ER stress signaling is altered. The N-terminal ubiquitin-like domain is required for cell survival under ER stress. Herp knockout cells (F9 embryonic carcinoma), ERAD substrate stability assays, transfection rescue with ULD mutants Genes to cells High 15147274
2004 HERPUD1 (Herp) stabilizes ER calcium homeostasis in neurons during ER stress, prevents ER Ca2+ overload, attenuates agonist-induced ER Ca2+ release, and preserves mitochondrial function. Knockdown sensitizes neurons to ER stress-induced apoptosis; overexpression is neuroprotective. Caspase cleavage of Herp (generating a 30-kDa fragment) is an early event in lethal ER stress; mutagenesis of the caspase cleavage site enhances neuroprotection. RNA interference, overexpression, Ca2+ imaging, caspase mutagenesis, mitochondrial function assays, apoptosis assays The Journal of biological chemistry High 15102845
2005 HERPUD1 (HERP) forms a high-molecular-mass complex in the ER membrane with the ubiquitin ligase HRD1, the retrotranslocation factors p97, Derlin-1, and VIMP. HERP binds directly to HRD1, while p97 interacts with Derlin-1 and HRD1 directly. Co-immunoprecipitation, pulldown assays, protein complex characterization Journal of molecular biology High 16289116
2006 Luman/CREB3 transcription factor, activated by ER stress (thapsigargin-induced proteolytic processing), directly binds the ERSE-II element (ATTGG-N-CCACG) in the HERPUD1 promoter and transcriptionally activates HERPUD1 expression. Luman knockdown or dominant-negative mutant attenuates Herp induction during ER stress. Chromatin immunoprecipitation (ChIP), promoter mutagenesis, siRNA knockdown, reporter assays Molecular and cellular biology High 16940180
2007 HERPUD1 (Herp) is part of an ERAD pathway for nonglycosylated BiP substrates. Herp associates with ubiquitinated substrates and with the 26S proteasome, and is in a complex with Derlin-1 and Hrd1. Depletion of Herp stabilizes BiP substrates but not calnexin substrates, indicating substrate-specific pathway usage. Co-immunoprecipitation, siRNA knockdown, ERAD substrate stability assays, cell biology Molecular cell High 18042451
2007 HERPUD1 (Herp) is both a substrate and an activator of the E3 ubiquitin ligase POSH. Herp-mediated POSH activation requires the UBL domain and promotes exclusively lysine-63-linked polyubiquitination. Under basal conditions, Herp localizes primarily to the trans-Golgi network; calcium perturbation (thapsigargin) causes POSH-dependent K63-ubiquitination of Herp and its relocalization to the ER, which regulates calcium homeostasis. Confocal microscopy, dominant-negative POSH, in vitro ubiquitination assays, siRNA, calcium imaging The Journal of cell biology High 17420289
2008 HERPUD1 (Herp) interacts with members of the ubiquilin family (ubiquilin proteins, which shuttle ubiquitinated substrates to the proteasome). Ubiquilin knockdown stabilizes the ERAD substrate CD3delta. Herp mutants capable of ubiquilin binding but lacking the transmembrane domain also stabilize CD3delta, suggesting ubiquilin binding is important for ERAD substrate delivery. Co-immunoprecipitation, siRNA knockdown, ERAD substrate assays, deletion mutagenesis Biochemical and biophysical research communications Medium 18307982
2010 HERPUD1 (Herp) is rapidly degraded by Hrd1-dependent proteasomal degradation. Herp regulates Hrd1-mediated ubiquitylation in a UBL domain-dependent manner: the UBL domain is required for efficient ubiquitylation of the Hrd1 substrate NHK (alpha1-antitrypsin null Hong Kong). Multiple copies of Hrd1 exist in a single complex, enabling binding of variable numbers of Herp molecules. Hrd1-associated Herp undergoes continuous turnover. Co-immunoprecipitation, UBL domain mutagenesis, ubiquitylation assays, pulse-chase The Journal of biological chemistry High 21149444
2010 HERPUD1 (Herp) deletion facilitates degradation of cytosolic proteins such as alpha-synuclein and synphilin-1 during proteasomal stress. Herp transiently associates with alpha-synuclein, synphilin-1, and the E3 ligase SIAH1a during proteolytic stress but not during ER stress, suggesting Herp sequesters these substrates from ubiquitination. Herp knockdown and knockout cells, co-immunoprecipitation, protein degradation assays, cell viability Genes to cells Medium 20604806
2010 PRKCSH (glucosidase II beta subunit) interacts with HERPUD1 (Herp) and inhibits Herp-mediated ubiquitination of polycystin-2/TRPP2, thereby protecting TRPP2 from ERAD. This establishes HERPUD1 as an E3-related factor targeting TRPP2 for degradation. Co-immunoprecipitation, ubiquitination assays, zebrafish overexpression/depletion phenotyping Human molecular genetics Medium 19801576
2011 HERPUD1 (Herp) maintains ER calcium homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca2+ release channels (IP3Rs and RyRs). The UBL domain is required for this function. Knockdown of Herp leads to accumulation of IP3Rs/RyRs, elevated cytosolic Ca2+, and exacerbated ER stress in response to mutant alpha-synuclein. Pharmacological proteasome inhibition abolishes Herp-mediated Ca2+ stabilization. siRNA knockdown, UBL domain deletion mutagenesis, proteasome inhibition, Ca2+ imaging, Western blot for channel levels Human molecular genetics High 22045699
2012 Herp-deficient mice are viable but show impaired glucose tolerance, vulnerability to brain ischemic injury, and reduced degradation of ERAD substrates in the liver. ERAD-related protein expression is altered in multiple organs under both normal and stress conditions. Gene-targeted Herp-knockout mice, glucose tolerance testing, ischemia model, ERAD substrate assays PloS one High 22479592
2013 HERPUD1 (Herp) depletion leads to upregulation of Beclin-1 (due to reduced Hrd1-dependent proteasomal degradation of Beclin-1) and increased autophagic flux, which enhances clearance of polyubiquitin protein aggregates and protects cells from glucose starvation-induced death. Herp stable knockdown cells, autophagy flux assays, Beclin-1 protein stability, GFP-LC3 puncta, cell viability Biochimica et biophysica acta Medium 24120520
2013 HERPUD2 (HERP2), a constitutively expressed homolog of HERP1, together with HERP1, are required for efficient HRD1-mediated ERAD of lumenal substrates (SHH, NHK). HERPs interact with HRD1 through a cytosolic region, help recruit DERL2 to the HRD1-SEL1L complex, and facilitate substrate ubiquitination and retrotranslocation. In the absence of HERPs, substrates are trapped in the ER bound to HRD1-SEL1L. siRNA depletion, Co-immunoprecipitation, substrate stability and ubiquitination assays, reconstitution of complex The Journal of biological chemistry High 24366871
2014 HERPUD1 (Herp) localizes to the ER quality control compartment (ERQC) and is responsible for recruiting HRD1 to the ERQC, where HRD1 targets ERAD substrates presented by OS-9 lectin. The PERK branch of the UPR, which strongly induces Herp, is required for this HRD1 and misfolded protein compartmentalization. Fluorescence microscopy (localization to ERQC), siRNA knockdown, functional ERAD assays Molecular biology of the cell High 24478453
2014 HERPUD1 (HERP) is polyubiquitylated by the Ube2g2-gp78 E2-E3 pair via interaction between the CUE domain of gp78 and the UBL domain of HERP, leading to proteasomal degradation of HERP during ER stress recovery. This degradation is required for cell adaptation: high HERP levels reduce viability under oxidative stress. In vitro ubiquitylation assay, Co-immunoprecipitation (CUE-UBL interaction), siRNA, protein stability assays Journal of cell science High 24496447
2015 Nrf1 transcription factor is required for basal and ER stress-induced expression of HERPUD1. Nrf1 directly binds antioxidant response elements (AREs) in the Herpud1 promoter, as demonstrated by chromatin immunoprecipitation. Loss of Nrf1 decreases Herpud1 expression in cells and liver tissue. Nrf1 knockout cells, ChIP, promoter reporter/transactivation assays FEBS letters Medium 25637874
2015 HERPUD1 protects against oxidative stress-induced apoptosis by downregulating inositol 1,4,5-trisphosphate receptor (ITPR) levels, thereby reducing ER-to-mitochondria Ca2+ transfer. HERPUD1 knockdown leads to greater cytosolic and mitochondrial Ca2+ increases and higher apoptosis in response to H2O2; these effects are rescued by ITPR antagonism or intracellular Ca2+ chelation. Stable HERPUD1 knockdown, Ca2+ imaging (cytosolic and mitochondrial), pharmacological rescue with ITPR antagonists, mitochondrial permeability transition assays Free radical biology & medicine High 26616647
2017 Herpud1 negatively regulates pathological cardiac hypertrophy through facilitating IP3R1 degradation. Herpud1-knockout mice develop cardiac hypertrophy and dysfunction. Herpud1 siRNA in rat cardiomyocytes increases IP3R protein levels, elevates cytosolic and nuclear Ca2+, and increases hypertrophic markers. Herpud1-knockout mice, siRNA knockdown in cardiomyocytes, IP3R protein levels, Ca2+ imaging, cardiac phenotyping Scientific reports High 29042597
2017 HERPUD1 (HERP) interacts with TANK-binding kinase 1 (TBK1) and amplifies MAVS signaling during viral infection (EV71) and ER stress. HERP promotes phosphorylation and nuclear translocation of IRF3 and NF-κB, enhancing type-I and type-III IFN expression to suppress RNA virus replication. Co-immunoprecipitation (HERP-TBK1), knockdown/overexpression, IRF3/NF-κB phosphorylation and nuclear translocation assays, IFN reporter assays, viral replication assays Journal of immunology Medium 28954889
2018 HERPUD1 and ERAD are required for osteoblast differentiation and mineralization. HERPUD1 expression increases as osteoblasts mature; its absence blocks mineralization and reduces alkaline phosphatase activity in MC3T3-E1 cells and primary rat osteoblasts. Overexpression of HERPUD1 activates the osteoblast differentiation program. HERPUD1 knockdown and overexpression, calcium deposit assays, alkaline phosphatase activity, Runx2/osterix expression in MC3T3-E1 and primary osteoblasts FASEB journal Medium 29570393
2021 The p300/XBP1s/HERPUD1 axis promotes macrophage M2 polarization: hypoxia-induced p300 acetylates XBP1s (stabilizing it from proteasomal degradation), and XBP1s transcriptionally activates HERPUD1, which then promotes M2 polarization. Knockdown of any component inhibits VEGF-driven choroidal neovascularization. Co-immunoprecipitation (p300-XBP1s), acetylation assays, siRNA knockdown, macrophage polarization assays, angiogenesis assays, in vivo laser-induced CNV model Journal of cellular and molecular medicine Medium 34057287
2022 HERPUD1 reduces ubiquitination of the E3 ubiquitin ligase MDM2, which in turn promotes ubiquitination and degradation of glutathione synthetase (GSS), thereby inhibiting glutathione (GSH) synthesis and sensitizing liver cancer cells to ferroptosis. Corosolic acid (CA) acts through HERPUD1 to suppress tumor growth. siRNA knockdown, overexpression, ubiquitination assays (MDM2, GSS), GSH measurement, xenograft mouse model Cell death discovery Medium 36038536

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 HES and HERP families: multiple effectors of the Notch signaling pathway. Journal of cellular physiology 1015 12548545
2000 Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. The Journal of biological chemistry 271 10922362
2017 Principles of the Kenzan Method for Robotic Cell Spheroid-Based Three-Dimensional Bioprinting<sup/>. Tissue engineering. Part B, Reviews 206 27917703
2001 HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Molecular and cellular biology 185 11486045
2007 Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. Molecular cell 180 18042451
2005 The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. Journal of molecular biology 177 16289116
2001 HERP, a new primary target of Notch regulated by ligand binding. Molecular and cellular biology 172 11486044
1994 Molecular cloning and functional characterization of a human VIP receptor from SUP-T1 lymphoblasts. Biochemical and biophysical research communications 145 7811244
1997 SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling. Development (Cambridge, England) 139 9428412
2004 Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways. The Journal of biological chemistry 135 14742429
2006 Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcoholism, clinical and experimental research 128 16573575
2017 Comparison of 3D-Printed Poly-ɛ-Caprolactone Scaffolds Functionalized with Tricalcium Phosphate, Hydroxyapatite, Bio-Oss, or Decellularized Bone Matrix<sup/>. Tissue engineering. Part A 124 28027692
2002 Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. The Journal of biological chemistry 121 11799129
2006 Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. Molecular and cellular biology 117 16940180
2018 Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database<sup/>. Critical reviews in toxicology 112 29474128
2004 Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. The Journal of biological chemistry 109 15102845
2004 Role of Herp in the endoplasmic reticulum stress response. Genes to cells : devoted to molecular & cellular mechanisms 104 15147274
2006 Characterization of a novel putative zinc finger gene MIF1: involvement in multiple hormonal regulation of Arabidopsis development. The Plant journal : for cell and molecular biology 96 16412086
2017 Fabrication of a Highly Aligned Neural Scaffold via a Table Top Stereolithography 3D Printing and Electrospinning<sup/>. Tissue engineering. Part A 93 27998214
1981 A second informational suppressor, SUP-7 X, in Caenorhabditis elegans. Genetics 91 7274656
1994 Mutations in the SUP-PF-1 locus of Chlamydomonas reinhardtii identify a regulatory domain in the beta-dynein heavy chain. The Journal of cell biology 88 8089181
2007 The Fox-1 family and SUP-12 coordinately regulate tissue-specific alternative splicing in vivo. Molecular and cellular biology 80 17923701
2008 Herp enhances ER-associated protein degradation by recruiting ubiquilins. Biochemical and biophysical research communications 78 18307982
2000 Regulation of SUP expression identifies multiple regulators involved in arabidopsis floral meristem development. The Plant cell 76 11006335
1983 The genes sup-7 X and sup-5 III of C. elegans suppress amber nonsense mutations via altered transfer RNA. Cell 76 6571695
2016 The Scaffold Immune Microenvironment: Biomaterial-Mediated Immune Polarization in Traumatic and Nontraumatic Applications<sup/>. Tissue engineering. Part A 68 27736323
2009 Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies. Clinical neuropathology 68 19788048
2017 Evaluation of Sofosbuvir (β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine) as an inhibitor of Dengue virus replication<sup/>. Scientific reports 67 28740124
2014 Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD. Molecular biology of the cell 65 24478453
2018 CapZyme-Seq Comprehensively Defines Promoter-Sequence Determinants for RNA 5' Capping with NAD<sup/>. Molecular cell 64 29681497
2003 sup-9, sup-10, and unc-93 may encode components of a two-pore K+ channel that coordinates muscle contraction in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 64 14534247
1995 The unc-8 and sup-40 genes regulate ion channel function in Caenorhabditis elegans motorneurons. Genetics 62 7539392
2012 Derlin-1 deficiency is embryonic lethal, Derlin-3 deficiency appears normal, and Herp deficiency is intolerant to glucose load and ischemia in mice. PloS one 60 22479592
2010 Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like domain-dependent manner. The Journal of biological chemistry 60 21149444
1995 Halotolerance in Methanosarcina spp.: Role of N(sup(epsilon))-Acetyl-(beta)-Lysine, (alpha)-Glutamate, Glycine Betaine, and K(sup+) as Compatible Solutes for Osmotic Adaptation. Applied and environmental microbiology 60 16535193
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2006 Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in sporadic inclusion-body myositis and in endoplasmic reticulum stress-induced cultured human muscle fibers. Journal of neurochemistry 54 16441512
2004 The RNA-binding protein SUP-12 controls muscle-specific splicing of the ADF/cofilin pre-mRNA in C. elegans. The Journal of cell biology 50 15545320
2019 Memantine protects thalamocortical hyper-glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc<sup/>. Pharmacology research & perspectives 49 30784207
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2005 Evidence for functional redundancy between C. elegans ADAM proteins SUP-17/Kuzbanian and ADM-4/TACE. Developmental biology 43 16197940
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2015 HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor. Free radical biology & medicine 42 26616647
2010 PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation. Human molecular genetics 41 19801576
2008 The psychology of psychiatric genetics: evidence that positive emotions in females moderate genetic sensitivity to social stress associated with the BDNF Val-sup-6-sup-6Met polymorphism. Journal of abnormal psychology 41 18729623
2018 HERP depletion inhibits zearalenone-induced apoptosis through autophagy activation in mouse ovarian granulosa cells. Toxicology letters 40 30394307
2007 The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp. The Journal of cell biology 40 17420289
2000 The novel MMS-inducible gene Mif1/KIAA0025 is a target of the unfolded protein response pathway. FEBS letters 40 10708769
2018 Exercise Mitigates Alcohol Induced Endoplasmic Reticulum Stress Mediated Cognitive Impairment through ATF6-Herp Signaling. Scientific reports 39 29581524
2012 Muscle-specific splicing factors ASD-2 and SUP-12 cooperatively switch alternative pre-mRNA processing patterns of the ADF/cofilin gene in Caenorhabditis elegans. PLoS genetics 38 23071450
1989 Pharmacological characterization of the novel helodermin/VIP receptor present in human SUP-T1 lymphoma cell membranes. Regulatory peptides 38 2552509
2014 Ube2g2-gp78-mediated HERP polyubiquitylation is involved in ER stress recovery. Journal of cell science 37 24496447
2003 The ubiquitin-like domain of Herp is involved in Herp degradation, but not necessary for its enhancement of amyloid beta-protein generation. FEBS letters 37 14550564
2017 Reactive Oxygen Species Shielding Hydrogel for the Delivery of Adherent and Nonadherent Therapeutic Cell Types<sup/>. Tissue engineering. Part A 35 28394196
2022 Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells. Cell death discovery 34 36038536
2017 Electrospun Template Architecture and Composition Regulate Neutrophil NETosis In Vitro and In Vivo<sup/>. Tissue engineering. Part A 34 28068879
2017 Stromal Cell-Derived Factor-1 Accelerates Cartilage Defect Repairing by Recruiting Bone Marrow Mesenchymal Stem Cells and Promoting Chondrogenic Differentiation<sup/>. Tissue engineering. Part A 34 28478702
2010 Water stress induces up-regulation of DOF1 and MIF1 transcription factors and down-regulation of proteins involved in secondary metabolism in amaranth roots (Amaranthus hypochondriacus L.). Plant biology (Stuttgart, Germany) 33 21489098
1992 Mutations in the sup-38 gene of Caenorhabditis elegans suppress muscle-attachment defects in unc-52 mutants. Genetics 33 1427037
2018 The catalytic mechanism of electron-bifurcating electron transfer flavoproteins (ETFs) involves an intermediary complex with NAD<sup/>. The Journal of biological chemistry 32 30567738
1984 The sup-7(st5) X gene of Caenorhabditis elegans encodes a tRNATrpUAG amber suppressor. Proceedings of the National Academy of Sciences of the United States of America 32 6093119
2018 Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial<sup/>. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 31 30115553
2017 MiR-9-3p augments apoptosis induced by H2O2 through down regulation of Herpud1 in glioma. PloS one 30 28430789
2013 Herp depletion protects from protein aggregation by up-regulating autophagy. Biochimica et biophysica acta 30 24120520
1981 Selective effects of alpha-MSH and MIF-1 on the blood-brain barrier. Peptides 30 6117842
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2018 Application of combined porous tantalum scaffolds loaded with bone morphogenetic protein 7 to repair of osteochondral defect in rabbits<sup/>. International orthopaedics 28 29445961
2018 Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching. International journal of cardiology 28 30017525
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2017 In Vivo Immune Responses of Cross-Linked Electrospun Tilapia Collagen Membrane<sup/>. Tissue engineering. Part A 27 28375819
2013 A deficiency of Herp, an endoplasmic reticulum stress protein, suppresses atherosclerosis in ApoE knockout mice by attenuating inflammatory responses. PloS one 27 24204574
2021 The P300/XBP1s/Herpud1 axis promotes macrophage M2 polarization and the development of choroidal neovascularization. Journal of cellular and molecular medicine 26 34057287
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2017 Bone Morphogenetic Protein 2 Alters Osteogenesis and Anti-Inflammatory Profiles of Mesenchymal Stem Cells Induced by Microtextured Titanium In Vitro<sup/>. Tissue engineering. Part A 24 28351289
2017 MicroRNA-384-mediated Herpud1 upregulation promotes angiotensin II-induced endothelial cell apoptosis. Biochemical and biophysical research communications 24 28483519
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2017 Biomaterial Encapsulation Is Enhanced in the Early Stages of the Foreign Body Reaction During Conditional Macrophage Depletion in Transgenic Macrophage Fas-Induced Apoptosis Mice<sup/>. Tissue engineering. Part A 23 28090808
2017 Activation of Macrophages by Lipopolysaccharide for Assessing the Immunomodulatory Property of Biomaterials<sup/>. Tissue engineering. Part A 23 28346799
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2010 Somatic sex determination in Caenorhabditis elegans is modulated by SUP-26 repression of tra-2 translation. Proceedings of the National Academy of Sciences of the United States of America 23 20921392
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2014 Targeting miR-21 sensitizes Ph+ ALL Sup-b15 cells to imatinib-induced apoptosis through upregulation of PTEN. Biochemical and biophysical research communications 22 25451263
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2022 MIF1 and MIF2 Myostatin Peptide Inhibitors as Potent Muscle Mass Regulators. International journal of molecular sciences 21 35457038
2017 IRMPD Action Spectroscopy, ER-CID Experiments, and Theoretical Studies of Sodium Cationized Thymidine and 5-Methyluridine: Kinetic Trapping During the ESI Desolvation Process Preserves the Solution Structure of [Thd+Na]<sup/>. Journal of the American Society for Mass Spectrometry 21 28836109
2017 Extrinsic Calcitonin Gene-Related Peptide Inhibits Hyperoxia-Induced Alveolar Epithelial Type II Cells Apoptosis, Oxidative Stress, and Reactive Oxygen Species (ROS) Production by Enhancing Notch 1 and Homocysteine-Induced Endoplasmic Reticulum Protein (HERP) Expression. Medical science monitor : international medical journal of experimental and clinical research 21 29206808
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2022 HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways. BMC cancer 20 36544104
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2013 A novel mechanism regulating insulin secretion involving Herpud1 in mice. Diabetologia 20 23620059
1989 VIP and related peptides induce rapid homologous desensitization in the human lymphoma SUP T1 cell line. Peptides 20 2474155
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2018 A new role for HERPUD1 and ERAD activation in osteoblast differentiation and mineralization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 29570393
2017 HERP Binds TBK1 To Activate Innate Immunity and Repress Virus Replication in Response to Endoplasmic Reticulum Stress. Journal of immunology (Baltimore, Md. : 1950) 19 28954889
1987 MIF-1 and Tyr-MIF-1 augment GABA-stimulated benzodiazepine receptor binding. Peptides 19 2893356