{"gene":"HERPUD1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"HERPUD1 (Herp/Mif1) is an integral ER membrane protein with both N- and C-termini facing the cytoplasm, containing an N-terminal ubiquitin-like domain; it is strongly induced by ER stress agents (tunicamycin, thapsigargin, mercaptoethanol, A23187) and by homocysteine via the ER stress response pathway.","method":"Immunochemical analysis with Herp-specific antibodies, Western blot, mRNA expression analysis, membrane topology studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — original characterization paper with multiple orthogonal methods (antibody detection, topology assay, stress induction), replicated in subsequent work","pmids":["10922362"],"is_preprint":false},{"year":2000,"finding":"Mif1/HERPUD1 is a target of the unfolded protein response (UPR) pathway; its 5' flanking region contains a functional ER stress-responsive element (ERSE) sufficient for induction by tunicamycin. MMS activates Mif1 via a UPR-independent pathway. Overexpressed Mif1 protein localizes to the ER.","method":"Reporter gene assays with ERSE-containing promoter constructs, mRNA/protein induction analysis, subcellular localization by immunofluorescence","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter studies and localization in one lab, two orthogonal methods","pmids":["10708769"],"is_preprint":false},{"year":2002,"finding":"Herp physically interacts with both presenilin 1 (PS1) and presenilin 2 (PS2), and high Herp expression increases amyloid beta-protein (Aβ) generation in a presenilin-dependent manner; Herp was identified by a screen for cDNAs that increase gamma-cleavage.","method":"Co-immunoprecipitation, overexpression in cells with and without presenilin, Aβ ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional cell assay in single lab, replicated mechanistic context","pmids":["11799129"],"is_preprint":false},{"year":2003,"finding":"The ubiquitin-like domain (ULD) of Herp is involved in its rapid proteasome-dependent degradation but is not required for enhancement of Aβ generation or interaction with presenilin.","method":"ULD deletion mutagenesis, pulse-chase degradation assay, co-immunoprecipitation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with degradation assay and Co-IP, single lab","pmids":["14550564"],"is_preprint":false},{"year":2004,"finding":"Herp is dually regulated by both the ER stress-specific branches (Ire1/XBP-1 and ATF6-dependent) and the shared cellular stress branch (PERK/eIF-2alpha/ATF4-dependent) of the UPR. ATF4 is required for Herp induction when only the shared branch is activated, but not when both branches are active.","method":"Genetic epistasis using knockout/knockdown of UPR branch components, Northern blot, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection with multiple UPR branch mutants, multiple orthogonal methods, replicated concept","pmids":["14742429"],"is_preprint":false},{"year":2004,"finding":"Herp stabilizes ER Ca2+ homeostasis and mitochondrial function in neurons during ER stress; overexpression promotes survival by preventing ER Ca2+ overload and suppressing caspase-3 and caspase-12 activation. Lethal ER stress causes caspase-mediated cleavage of Herp, generating a 30-kDa fragment; mutation of the caspase cleavage site enhances neuroprotection.","method":"RNA interference knockdown, Herp overexpression, Ca2+ imaging, mitochondrial function assays, caspase activity assays, mutagenesis of caspase cleavage site","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, OE, Ca2+ imaging, mutagenesis), functionally validated in single rigorous study","pmids":["15102845"],"is_preprint":false},{"year":2004,"finding":"Herp knockout cells (F9) are more vulnerable to ER stress, show enhanced ER stress signaling and stabilization of an ERAD substrate in early stress, and are prone to apoptosis in late stress. The N-terminal ubiquitin-like domain of Herp is required for cell survival under ER stress. Herp itself is rapidly degraded by the proteasome.","method":"F9 Herp knockout cells via gene targeting, tunicamycin treatment, ERAD substrate stability assay, transfection with domain-deletion constructs","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus domain mutagenesis, multiple phenotypic readouts","pmids":["15147274"],"is_preprint":false},{"year":2005,"finding":"HERP forms a high-molecular-mass complex at the ER membrane containing the ubiquitin E3 ligase HRD1, retrotranslocation factors p97, Derlin-1, and VIMP. HERP binds directly to HRD1, while p97 interacts with Derlin-1 and HRD1.","method":"Co-immunoprecipitation, sucrose gradient sedimentation, pull-down assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and pull-down establishing direct binding partners, multiple components characterized","pmids":["16289116"],"is_preprint":false},{"year":2006,"finding":"Luman/CREB3, an ER membrane-bound transcription factor, directly activates Herp transcription through the ER stress response element II (ERSE-II; ATTGG-N-CCACG) in the Herp promoter. Luman physically associates with the ERSE-II second half-site. Luman knockdown attenuates Herp induction during ER stress.","method":"Chromatin immunoprecipitation (ChIP), promoter mutagenesis, siRNA knockdown, luciferase reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, mutagenesis, and siRNA knockdown in combination establish direct transcriptional regulation","pmids":["16940180"],"is_preprint":false},{"year":2007,"finding":"Herp is required for degradation of nonglycosylated BiP substrates but not calnexin substrates; Herp forms a complex with ubiquitinated proteins and the 26S proteasome, linking substrates to the proteasome. Herp associates with Derlin-1, and either p97/Hrd1 mutant expression or Herp knockdown inhibits BiP substrate degradation.","method":"Co-immunoprecipitation, siRNA knockdown, proteasome association assay, pulse-chase degradation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple substrates tested, reciprocal Co-IP, loss-of-function with defined substrate specificity, single rigorous study with multiple methods","pmids":["18042451"],"is_preprint":false},{"year":2007,"finding":"POSH, a ubiquitin E3 ligase, interacts with Herp and promotes K63-linked polyubiquitination of Herp via its UBL domain. This POSH-dependent ubiquitination controls Herp relocalization from the trans-Golgi network to the ER upon Ca2+ perturbation by thapsigargin, and regulates ER Ca2+ homeostasis.","method":"Co-immunoprecipitation, confocal microscopy, in vitro ubiquitination assay, dominant-negative overexpression, RNAi, Ca2+ measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro ubiquitination assay, confocal localization, dominant-negative and RNAi functional validation in single rigorous study","pmids":["17420289"],"is_preprint":false},{"year":2008,"finding":"Herp interacts with members of the ubiquilin family; this interaction is required for efficient ERAD of a subset of substrates (e.g., CD3δ). Herp mutants lacking the transmembrane domain but retaining ubiquilin-binding capacity stabilize CD3δ, indicating that ubiquilin recruitment by Herp facilitates substrate delivery to the proteasome.","method":"Co-immunoprecipitation, siRNA knockdown of ubiquilins, overexpression of Herp transmembrane domain deletion mutants, pulse-chase degradation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional degradation assay, single lab with two orthogonal methods","pmids":["18307982"],"is_preprint":false},{"year":2010,"finding":"Herp regulates Hrd1-mediated ubiquitylation in a UBL domain-dependent manner; the Herp UBL domain is required for efficient ubiquitylation and degradation of the Hrd1-specific ERAD substrate NHK (null Hong Kong α1-antitrypsin). Upon ER stress, Herp is rapidly degraded and substituted by newly synthesized Herp at Hrd1 complexes, and multiple Hrd1 copies in a complex can bind variable numbers of Herp molecules.","method":"UBL domain mutagenesis, co-immunoprecipitation, pulse-chase assay, ubiquitylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of functional domain combined with ubiquitylation assay and degradation assay, clear mechanistic conclusion","pmids":["21149444"],"is_preprint":false},{"year":2010,"finding":"Herp knockdown facilitates degradation of cytosolic proteins (α-synuclein, synphilin-1) and improves cell viability during proteasomal inhibition. Herp transiently binds α-synuclein, synphilin-1, and the E3 ligase SIAH1a during proteolytic stress (but not during ER stress), suggesting Herp delays ubiquitination of cytosolic substrates.","method":"siRNA knockdown, F9 Herp knockout cells, co-immunoprecipitation, protein stability assay, cell viability assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and KD with substrate assay, Co-IP for interaction, single lab","pmids":["20604806"],"is_preprint":false},{"year":2011,"finding":"Herp maintains ER Ca2+ homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca2+ release channels (IP3 receptors and ryanodine receptors). UBL domain deletion or proteasome inhibition abolishes Herp-mediated ER Ca2+ stabilization. Aberrant accumulation of Ca2+ channels and chronic ER stress are observed in mutant A53T-αSyn transgenic mice.","method":"siRNA knockdown, UBL domain deletion, pharmacological proteasome inhibition, Ca2+ imaging, Western blot for IP3R/RyR levels, transgenic mouse model","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, mutagenesis, pharmacological inhibition, in vivo model), clear mechanistic pathway established","pmids":["22045699"],"is_preprint":false},{"year":2012,"finding":"Herp-deficient mice are viable but exhibit impaired glucose tolerance and increased vulnerability to brain ischemia. In Herp-deficient liver, degradation of ERAD substrates is reduced. Herp deficiency affects expression of ERAD-related proteins in a tissue-specific manner.","method":"Gene targeting knockout mice, glucose tolerance test, ischemia model, ERAD substrate stability assay, Western blot","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with defined physiological phenotypes and molecular readouts","pmids":["22479592"],"is_preprint":false},{"year":2013,"finding":"Herp localizes to the ER quality control compartment (ERQC) and recruits HRD1 to this compartment; Herp is responsible for compartmentalization of misfolded proteins and the ubiquitin ligase HRD1 required for ERAD. Predicted structural similarity to ubiquitin-proteasome shuttle hHR23 (but with a transmembrane hairpin) suggests Herp functions as a membrane-anchored hub for ERAD machinery assembly.","method":"Immunofluorescence microscopy, siRNA knockdown, co-localization analysis, structural bioinformatics","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional KD, structural prediction provides supporting rationale","pmids":["24478453"],"is_preprint":false},{"year":2013,"finding":"HERP1 (HERPUD1) and HERP2 are both required for efficient HRD1-dependent ERAD of lumenal substrates (SHH, NHK). HERP2 is constitutively expressed while HERP1 is ER stress-induced. Both HERPs interact with HRD1 through a cytosol-facing region and help recruit DERL2 to the HRD1-SEL1L complex to form an active retrotranslocation complex. The UBL domain of HERP1 has an additional DERL2-independent function in ERAD.","method":"siRNA double knockdown, co-immunoprecipitation, ubiquitination assay, retrotranslocation assay, pulse-chase degradation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple substrates, double KD, Co-IP, ubiquitination and retrotranslocation assays in single rigorous study","pmids":["24366871"],"is_preprint":false},{"year":2013,"finding":"Herp depletion leads to upregulation of autophagy regulators Atg5 and Beclin-1 (the latter via reduced Hrd1-dependent proteasomal degradation), resulting in increased autophagic flux that clears poly-ubiquitin protein aggregates and protects cells from glucose starvation-induced death.","method":"Stable shRNA knockdown, LC3-II Western blot, GFP-LC3 puncta assay, protein aggregation assay, cell viability assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable KD with multiple autophagy readouts and mechanistic explanation, single lab","pmids":["24120520"],"is_preprint":false},{"year":2014,"finding":"gp78 (an ER E3 ubiquitin ligase) together with Ube2g2 mediates polyubiquitylation of HERP, driven by a physical interaction between the CUE domain of gp78 and the UBL domain of HERP, leading to proteasomal degradation of HERP during ER stress recovery.","method":"In vitro ubiquitylation assay, co-immunoprecipitation, domain interaction mapping (CUE-UBL), siRNA knockdown, pulse-chase assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitylation plus domain-level interaction mapping and in vivo validation","pmids":["24496447"],"is_preprint":false},{"year":2015,"finding":"Nrf1 transcription factor directly activates Herpud1 expression during ER stress through antioxidant response elements in the Herpud1 promoter; loss of Nrf1 decreases Herpud1 expression and abolishes its ER stress induction.","method":"Nrf1 knockout cells, chromatin immunoprecipitation (ChIP), transactivation reporter assays, liver tissue analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct binding, KO cells, and transactivation assays provide convergent evidence","pmids":["25637874"],"is_preprint":false},{"year":2015,"finding":"HERPUD1 protects against oxidative stress-induced apoptosis by downregulating IP3 receptor (ITPR)-mediated Ca2+ release from the ER; HERPUD1 knockdown increases cytosolic and mitochondrial Ca2+ and cell death, which is abolished by ITPR antagonism or intracellular Ca2+ chelation.","method":"Stable shRNA knockdown, flow cytometry (cell death), Ca2+ imaging (cytosolic and mitochondrial), ITPR pharmacological inhibition, BAPTA-AM chelation","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with Ca2+ imaging and pharmacological rescue, single lab","pmids":["26616647"],"is_preprint":false},{"year":2017,"finding":"HERP interacts with TBK1 (TANK-binding kinase 1) and amplifies MAVS signaling, facilitating phosphorylation and nuclear translocation of IRF3 and NF-κB to enhance type-I and type-III IFN expression and inhibit RNA virus replication. HERP induction by EV71 is dependent on MAVS.","method":"Co-immunoprecipitation, reporter assays for IFN promoters, phosphorylation assays, nuclear translocation by immunofluorescence, siRNA knockdown, virus replication assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and multiple downstream signaling readouts in single lab","pmids":["28954889"],"is_preprint":false},{"year":2017,"finding":"Herpud1 knockout mice develop cardiac hypertrophy and dysfunction; Herpud1 deficiency elevates IP3R protein levels and increases cytosolic and nuclear Ca2+ in cardiomyocytes. Herpud1 negatively regulates cardiac hypertrophy by promoting IP3R degradation via the ERAD pathway.","method":"Herpud1 knockout mouse model, echocardiography, siRNA knockdown in cardiomyocytes, IP3R Western blot, Ca2+ imaging, hypertrophic marker expression","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout combined with in vitro KD, multiple orthogonal readouts (IP3R levels, Ca2+, hypertrophic markers)","pmids":["29042597"],"is_preprint":false},{"year":2018,"finding":"HERPUD1 is required for osteoblast differentiation and mineralization; its expression increases as differentiation progresses with activation of ERAD and proteasomal degradation. HERPUD1 absence blocks mineralization and reduces alkaline phosphatase activity, while overexpression activates the osteoblast differentiation program.","method":"siRNA knockdown, overexpression in MC3T3-E1 and primary osteoblasts, alkaline phosphatase activity assay, calcium deposit measurement, Runx2/osterix expression","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with multiple differentiation readouts, single lab","pmids":["29570393"],"is_preprint":false},{"year":2010,"finding":"PRKCSH (glucosidase II beta subunit) interacts with HERP and inhibits HERP-mediated ubiquitination of TRPP2/polycystin-2, thereby protecting TRPP2 from ERAD; PRKCSH co-localizes with TRPP2 in the ER and binds TRPP2's C-terminal domain.","method":"Co-immunoprecipitation, ubiquitination assay, zebrafish overexpression/depletion, co-localization by immunofluorescence","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro ubiquitination inhibition, and zebrafish epistasis, single lab","pmids":["19801576"],"is_preprint":false},{"year":2006,"finding":"Homocysteine-induced epigenetic hypermethylation of the HERP promoter correlates with decreased HERP mRNA expression, and promoter CpG island methylation is sufficient to suppress Herp transcription. Acute homocysteine causes transient promoter demethylation and Herp induction; the AARE and CREB binding sites in the Herp promoter mediate homocysteine-induced transcription.","method":"Luciferase reporter assays with AARE/CREB site mutations, methylation-specific PCR, mRNA quantitative PCR in patient samples and cell lines","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of promoter elements combined with methylation analysis and expression data","pmids":["17020760"],"is_preprint":false},{"year":2021,"finding":"Hypoxia-induced p300 acetyltransferase interacts with and acetylates XBP1s, enhancing XBP1s stability and its transcriptional activation of Herpud1 through ERSE-II. The p300/XBP1s/Herpud1 axis promotes M2 macrophage polarization.","method":"Co-immunoprecipitation, acetylation assay, ChIP/promoter reporter assay, siRNA knockdown, macrophage polarization assay, mouse laser-induced CNV model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, acetylation assay, and functional downstream readouts in single lab","pmids":["34057287"],"is_preprint":false},{"year":2022,"finding":"HERPUD1 promotes ferroptosis sensitivity in liver cancer cells by reducing MDM2 ubiquitination of glutathione synthetase (GSS), leading to GSS ubiquitination/degradation and decreased glutathione (GSH) levels, thus increasing susceptibility to ferroptosis.","method":"Overexpression/knockdown, ubiquitination assay for GSS/MDM2 interaction, GSH measurement, ferroptosis sensitivity assay, mouse xenograft model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with in vivo validation, single lab","pmids":["36038536"],"is_preprint":false},{"year":2013,"finding":"Herpud1 regulates insulin secretion in pancreatic beta cells; Herpud1 knockdown in DBA/2 islets reduces glucose-stimulated insulin secretion and decreases Nnt expression, while Herpud1 overexpression increases Nnt expression, placing Herpud1 upstream of Nnt in insulin secretion regulation.","method":"siRNA knockdown, Herpud1 overexpression in MIN6 cells and DBA/2 islets, glucose-stimulated insulin secretion assay, microarray profiling","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined functional readout, genetic epistasis with Nnt, single lab","pmids":["23620059"],"is_preprint":false}],"current_model":"HERPUD1 (Herp/Mif1) is an ER-resident integral membrane protein with a cytoplasm-facing N-terminal ubiquitin-like domain (UBL) that is strongly induced by ER stress via multiple UPR branches (ATF6/XBP1, PERK/ATF4) and by transcription factors including Luman/CREB3 and Nrf1; it functions as a scaffolding hub of the ERAD multiprotein complex by directly binding the E3 ubiquitin ligase HRD1 and recruiting DERL2, p97, and ubiquilins to facilitate retrotranslocation and proteasomal degradation of misfolded ER proteins; it also maintains ER Ca2+ homeostasis by promoting ERAD-dependent degradation of IP3 receptors (limiting Ca2+ release to the cytosol and mitochondria); its own turnover is regulated by gp78/Ube2g2-mediated K48-linked ubiquitylation (through CUE domain–UBL domain interaction) and by POSH-mediated K63-linked ubiquitylation that controls its localization; and it plays roles in innate immune signaling by binding TBK1 to amplify MAVS/IRF3/NF-κB-dependent IFN production during viral infection."},"narrative":{"mechanistic_narrative":"HERPUD1 (Herp/Mif1) is an ER-resident integral membrane protein with a cytoplasm-facing N-terminal ubiquitin-like domain that serves as a stress-inducible scaffolding hub of the ER-associated degradation (ERAD) machinery [PMID:10922362, PMID:16289116]. It is among the most strongly induced targets of the unfolded protein response, regulated combinatorially through both the IRE1/XBP1 and ATF6 ER-stress branches and the shared PERK/eIF2α/ATF4 branch [PMID:14742429], and through additional transcription factors acting at its promoter elements, including Luman/CREB3 at ERSE-II and Nrf1 at antioxidant response elements [PMID:16940180, PMID:25637874]. Mechanistically, HERPUD1 assembles a high-molecular-mass ERAD complex by binding directly to the E3 ubiquitin ligase HRD1 and recruiting the retrotranslocation factors p97, Derlin/DERL2 and VIMP, and by engaging ubiquilins to deliver substrates to the 26S proteasome [PMID:16289116, PMID:18042451, PMID:18307982, PMID:24366871]. Its UBL domain is required for efficient HRD1-mediated ubiquitylation and degradation of lumenal substrates such as NHK α1-antitrypsin, and HERPUD1 compartmentalizes misfolded proteins and HRD1 within the ER quality control compartment, where it acts as a membrane-anchored shuttle analogous to hHR23 [PMID:21149444, PMID:24478453, PMID:24366871]. Through ERAD-dependent turnover of ER Ca2+ release channels, principally IP3 receptors, HERPUD1 limits Ca2+ release to the cytosol and mitochondria, protecting cells against ER-stress- and oxidative-stress-induced apoptosis [PMID:15102845, PMID:22045699, PMID:26616647]; loss of this function in vivo produces impaired glucose tolerance, ischemic vulnerability, and cardiac hypertrophy with elevated IP3R levels [PMID:22479592, PMID:29042597]. HERPUD1 is itself a short-lived protein whose UBL domain drives rapid proteasomal turnover, including gp78/Ube2g2-mediated K48-linked ubiquitylation during ER-stress recovery and POSH-mediated K63-linked ubiquitylation that governs its trafficking between the trans-Golgi network and ER upon Ca2+ perturbation [PMID:14550564, PMID:17420289, PMID:24496447]. Beyond core ERAD, HERPUD1 binds TBK1 to amplify MAVS-dependent IRF3/NF-κB signaling and type-I/III interferon production during RNA virus infection [PMID:28954889].","teleology":[{"year":2000,"claim":"Established the basic identity of HERPUD1 as a stress-inducible ER membrane protein, defining the molecular object before any function was known.","evidence":"Antibody detection, membrane topology assays and stress induction in cultured cells; promoter reporter assays mapping a functional ERSE","pmids":["10922362","10708769"],"confidence":"High","gaps":["Cytoplasmic function of the UBL domain not yet defined","No binding partners identified"]},{"year":2002,"claim":"First physical interactions and a functional context were assigned, linking Herp to presenilins and amyloid processing.","evidence":"Co-immunoprecipitation, overexpression and Aβ ELISA in presenilin-dependent cells; ULD deletion mapping","pmids":["11799129","14550564"],"confidence":"Medium","gaps":["UBL/ULD role in Aβ generation dissociated from degradation but mechanism unclear","Single-lab Co-IP without reciprocal validation in independent systems"]},{"year":2004,"claim":"Resolved how HERPUD1 is induced and showed it is cytoprotective during ER stress, connecting transcriptional control to a survival phenotype.","evidence":"Genetic epistasis across UPR branch mutants; RNAi, overexpression, Ca2+ imaging, caspase assays and knockout F9 cells","pmids":["14742429","15102845","15147274"],"confidence":"High","gaps":["Molecular basis of Ca2+ stabilization not yet defined","ERAD substrate spectrum not delineated"]},{"year":2005,"claim":"Defined HERPUD1 as a direct binding partner of HRD1 within a retrotranslocation complex, establishing its scaffolding role in ERAD.","evidence":"Reciprocal Co-IP, sucrose gradient sedimentation and pull-down assays","pmids":["16289116"],"confidence":"High","gaps":["Substrate specificity of the complex not addressed","Stoichiometry of HERP within the complex unknown"]},{"year":2007,"claim":"Defined substrate selectivity and the proteasome-linking function, and identified POSH-mediated K63 ubiquitylation controlling HERP localization.","evidence":"siRNA knockdown, reciprocal Co-IP, proteasome association and pulse-chase assays for BiP-substrate ERAD; in vitro ubiquitination and confocal localization for POSH","pmids":["18042451","17420289"],"confidence":"High","gaps":["Why HERP serves nonglycosylated/BiP but not calnexin substrates unresolved","Trigger linking Ca2+ perturbation to POSH ubiquitylation not defined"]},{"year":2006,"claim":"Identified Luman/CREB3 as a direct transcriptional activator at ERSE-II, expanding the regulatory inputs beyond the canonical UPR triad.","evidence":"ChIP, promoter mutagenesis, siRNA knockdown and luciferase reporter assays","pmids":["16940180"],"confidence":"High","gaps":["Relative contribution of Luman versus ATF6/XBP1/ATF4 in vivo unclear"]},{"year":2008,"claim":"Showed ubiquilin recruitment by HERP is the link delivering specific substrates to the proteasome, mechanistically connecting scaffold to degradation.","evidence":"Co-IP, ubiquilin siRNA knockdown and transmembrane-deletion mutant rescue with pulse-chase degradation","pmids":["18307982"],"confidence":"Medium","gaps":["Substrate subset requiring ubiquilins not fully mapped","Single-lab evidence"]},{"year":2010,"claim":"Established UBL-domain-dependent regulation of HRD1 ubiquitylation and HERP's role in degrading ER Ca2+ release channels, unifying ERAD scaffolding with Ca2+ homeostasis.","evidence":"UBL mutagenesis, ubiquitylation and pulse-chase assays for NHK; KD, UBL deletion, proteasome inhibition, Ca2+ imaging and A53T-αSyn transgenic mice for IP3R/RyR turnover","pmids":["21149444","22045699"],"confidence":"High","gaps":["How HERP selects channel substrates not defined","Direct versus indirect role in channel ubiquitylation not separated"]},{"year":2013,"claim":"Defined HERPUD1's spatial role in the ERQC, its redundancy with HERP2, and a DERL2-recruitment mechanism, refining the architecture of the active retrotranslocation complex.","evidence":"Immunofluorescence/co-localization with KD; double siRNA knockdown, Co-IP, ubiquitination and retrotranslocation assays across multiple substrates","pmids":["24478453","24366871"],"confidence":"High","gaps":["Structural model of the membrane-anchored hub is predictive only","DERL2-independent UBL function not mechanistically explained"]},{"year":2014,"claim":"Mapped the CUE-UBL interaction driving gp78/Ube2g2-mediated K48 ubiquitylation, explaining HERP's own rapid turnover during stress recovery.","evidence":"In vitro ubiquitylation reconstitution, domain-interaction mapping, siRNA and pulse-chase","pmids":["24496447"],"confidence":"High","gaps":["Coordination between gp78-driven and POSH-driven ubiquitylation unresolved"]},{"year":2017,"claim":"Extended HERPUD1 function beyond ERAD into innate immunity and into in vivo cardiac physiology, broadening its biological scope.","evidence":"Co-IP, IFN reporter, phosphorylation and nuclear translocation assays with virus replication for TBK1/MAVS; knockout mice, echocardiography, KD, IP3R Western and Ca2+ imaging for cardiac hypertrophy","pmids":["28954889","29042597"],"confidence":"Medium","gaps":["Direct versus scaffold-mediated role in TBK1 signaling unclear","Single-lab evidence for the immune axis"]},{"year":2022,"claim":"Implicated HERPUD1 in non-canonical contexts including ferroptosis, osteoblast differentiation, autophagy and metabolic regulation, indicating context-dependent roles.","evidence":"Knockdown/overexpression with ubiquitination, GSH and ferroptosis assays; differentiation, autophagy flux, and insulin-secretion readouts across separate studies","pmids":["36038536","29570393","24120520","23620059"],"confidence":"Medium","gaps":["Whether these phenotypes depend on the core ERAD/Ca2+ functions not resolved","Each context characterized in a single study"]},{"year":null,"claim":"How HERPUD1's substrate selection, its self-turnover by competing ubiquitin ligases, and its diverse non-ERAD activities are mechanistically integrated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental structure of the membrane-anchored HERP-HRD1 complex","Rules governing substrate channeling to ubiquilins versus DERL2 undefined","Mechanistic link between Ca2+ regulation and the immune/metabolic roles unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,9,16,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,14,17]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,7,16]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,9,12,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22]}],"complexes":["HRD1-SEL1L ERAD complex"],"partners":["HRD1","DERL2","P97/VCP","VIMP","POSH","GP78","UBQLN","TBK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15011","full_name":"Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein","aliases":["Methyl methanesulfonate (MMF)-inducible fragment protein 1"],"length_aa":391,"mass_kda":43.7,"function":"Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (PubMed:16289116, PubMed:28827405). Could enhance presenilin-mediated amyloid-beta protein 40 generation. 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it is strongly induced by ER stress agents (tunicamycin, thapsigargin, mercaptoethanol, A23187) and by homocysteine via the ER stress response pathway.\",\n      \"method\": \"Immunochemical analysis with Herp-specific antibodies, Western blot, mRNA expression analysis, membrane topology studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original characterization paper with multiple orthogonal methods (antibody detection, topology assay, stress induction), replicated in subsequent work\",\n      \"pmids\": [\"10922362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mif1/HERPUD1 is a target of the unfolded protein response (UPR) pathway; its 5' flanking region contains a functional ER stress-responsive element (ERSE) sufficient for induction by tunicamycin. MMS activates Mif1 via a UPR-independent pathway. Overexpressed Mif1 protein localizes to the ER.\",\n      \"method\": \"Reporter gene assays with ERSE-containing promoter constructs, mRNA/protein induction analysis, subcellular localization by immunofluorescence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter studies and localization in one lab, two orthogonal methods\",\n      \"pmids\": [\"10708769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Herp physically interacts with both presenilin 1 (PS1) and presenilin 2 (PS2), and high Herp expression increases amyloid beta-protein (Aβ) generation in a presenilin-dependent manner; Herp was identified by a screen for cDNAs that increase gamma-cleavage.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in cells with and without presenilin, Aβ ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional cell assay in single lab, replicated mechanistic context\",\n      \"pmids\": [\"11799129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The ubiquitin-like domain (ULD) of Herp is involved in its rapid proteasome-dependent degradation but is not required for enhancement of Aβ generation or interaction with presenilin.\",\n      \"method\": \"ULD deletion mutagenesis, pulse-chase degradation assay, co-immunoprecipitation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with degradation assay and Co-IP, single lab\",\n      \"pmids\": [\"14550564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Herp is dually regulated by both the ER stress-specific branches (Ire1/XBP-1 and ATF6-dependent) and the shared cellular stress branch (PERK/eIF-2alpha/ATF4-dependent) of the UPR. ATF4 is required for Herp induction when only the shared branch is activated, but not when both branches are active.\",\n      \"method\": \"Genetic epistasis using knockout/knockdown of UPR branch components, Northern blot, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection with multiple UPR branch mutants, multiple orthogonal methods, replicated concept\",\n      \"pmids\": [\"14742429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Herp stabilizes ER Ca2+ homeostasis and mitochondrial function in neurons during ER stress; overexpression promotes survival by preventing ER Ca2+ overload and suppressing caspase-3 and caspase-12 activation. Lethal ER stress causes caspase-mediated cleavage of Herp, generating a 30-kDa fragment; mutation of the caspase cleavage site enhances neuroprotection.\",\n      \"method\": \"RNA interference knockdown, Herp overexpression, Ca2+ imaging, mitochondrial function assays, caspase activity assays, mutagenesis of caspase cleavage site\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, OE, Ca2+ imaging, mutagenesis), functionally validated in single rigorous study\",\n      \"pmids\": [\"15102845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Herp knockout cells (F9) are more vulnerable to ER stress, show enhanced ER stress signaling and stabilization of an ERAD substrate in early stress, and are prone to apoptosis in late stress. The N-terminal ubiquitin-like domain of Herp is required for cell survival under ER stress. Herp itself is rapidly degraded by the proteasome.\",\n      \"method\": \"F9 Herp knockout cells via gene targeting, tunicamycin treatment, ERAD substrate stability assay, transfection with domain-deletion constructs\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus domain mutagenesis, multiple phenotypic readouts\",\n      \"pmids\": [\"15147274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HERP forms a high-molecular-mass complex at the ER membrane containing the ubiquitin E3 ligase HRD1, retrotranslocation factors p97, Derlin-1, and VIMP. HERP binds directly to HRD1, while p97 interacts with Derlin-1 and HRD1.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient sedimentation, pull-down assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and pull-down establishing direct binding partners, multiple components characterized\",\n      \"pmids\": [\"16289116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Luman/CREB3, an ER membrane-bound transcription factor, directly activates Herp transcription through the ER stress response element II (ERSE-II; ATTGG-N-CCACG) in the Herp promoter. Luman physically associates with the ERSE-II second half-site. Luman knockdown attenuates Herp induction during ER stress.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter mutagenesis, siRNA knockdown, luciferase reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, mutagenesis, and siRNA knockdown in combination establish direct transcriptional regulation\",\n      \"pmids\": [\"16940180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Herp is required for degradation of nonglycosylated BiP substrates but not calnexin substrates; Herp forms a complex with ubiquitinated proteins and the 26S proteasome, linking substrates to the proteasome. Herp associates with Derlin-1, and either p97/Hrd1 mutant expression or Herp knockdown inhibits BiP substrate degradation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, proteasome association assay, pulse-chase degradation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple substrates tested, reciprocal Co-IP, loss-of-function with defined substrate specificity, single rigorous study with multiple methods\",\n      \"pmids\": [\"18042451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"POSH, a ubiquitin E3 ligase, interacts with Herp and promotes K63-linked polyubiquitination of Herp via its UBL domain. This POSH-dependent ubiquitination controls Herp relocalization from the trans-Golgi network to the ER upon Ca2+ perturbation by thapsigargin, and regulates ER Ca2+ homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, in vitro ubiquitination assay, dominant-negative overexpression, RNAi, Ca2+ measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro ubiquitination assay, confocal localization, dominant-negative and RNAi functional validation in single rigorous study\",\n      \"pmids\": [\"17420289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Herp interacts with members of the ubiquilin family; this interaction is required for efficient ERAD of a subset of substrates (e.g., CD3δ). Herp mutants lacking the transmembrane domain but retaining ubiquilin-binding capacity stabilize CD3δ, indicating that ubiquilin recruitment by Herp facilitates substrate delivery to the proteasome.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of ubiquilins, overexpression of Herp transmembrane domain deletion mutants, pulse-chase degradation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional degradation assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"18307982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Herp regulates Hrd1-mediated ubiquitylation in a UBL domain-dependent manner; the Herp UBL domain is required for efficient ubiquitylation and degradation of the Hrd1-specific ERAD substrate NHK (null Hong Kong α1-antitrypsin). Upon ER stress, Herp is rapidly degraded and substituted by newly synthesized Herp at Hrd1 complexes, and multiple Hrd1 copies in a complex can bind variable numbers of Herp molecules.\",\n      \"method\": \"UBL domain mutagenesis, co-immunoprecipitation, pulse-chase assay, ubiquitylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of functional domain combined with ubiquitylation assay and degradation assay, clear mechanistic conclusion\",\n      \"pmids\": [\"21149444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Herp knockdown facilitates degradation of cytosolic proteins (α-synuclein, synphilin-1) and improves cell viability during proteasomal inhibition. Herp transiently binds α-synuclein, synphilin-1, and the E3 ligase SIAH1a during proteolytic stress (but not during ER stress), suggesting Herp delays ubiquitination of cytosolic substrates.\",\n      \"method\": \"siRNA knockdown, F9 Herp knockout cells, co-immunoprecipitation, protein stability assay, cell viability assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and KD with substrate assay, Co-IP for interaction, single lab\",\n      \"pmids\": [\"20604806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Herp maintains ER Ca2+ homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca2+ release channels (IP3 receptors and ryanodine receptors). UBL domain deletion or proteasome inhibition abolishes Herp-mediated ER Ca2+ stabilization. Aberrant accumulation of Ca2+ channels and chronic ER stress are observed in mutant A53T-αSyn transgenic mice.\",\n      \"method\": \"siRNA knockdown, UBL domain deletion, pharmacological proteasome inhibition, Ca2+ imaging, Western blot for IP3R/RyR levels, transgenic mouse model\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, mutagenesis, pharmacological inhibition, in vivo model), clear mechanistic pathway established\",\n      \"pmids\": [\"22045699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Herp-deficient mice are viable but exhibit impaired glucose tolerance and increased vulnerability to brain ischemia. In Herp-deficient liver, degradation of ERAD substrates is reduced. Herp deficiency affects expression of ERAD-related proteins in a tissue-specific manner.\",\n      \"method\": \"Gene targeting knockout mice, glucose tolerance test, ischemia model, ERAD substrate stability assay, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with defined physiological phenotypes and molecular readouts\",\n      \"pmids\": [\"22479592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Herp localizes to the ER quality control compartment (ERQC) and recruits HRD1 to this compartment; Herp is responsible for compartmentalization of misfolded proteins and the ubiquitin ligase HRD1 required for ERAD. Predicted structural similarity to ubiquitin-proteasome shuttle hHR23 (but with a transmembrane hairpin) suggests Herp functions as a membrane-anchored hub for ERAD machinery assembly.\",\n      \"method\": \"Immunofluorescence microscopy, siRNA knockdown, co-localization analysis, structural bioinformatics\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional KD, structural prediction provides supporting rationale\",\n      \"pmids\": [\"24478453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HERP1 (HERPUD1) and HERP2 are both required for efficient HRD1-dependent ERAD of lumenal substrates (SHH, NHK). HERP2 is constitutively expressed while HERP1 is ER stress-induced. Both HERPs interact with HRD1 through a cytosol-facing region and help recruit DERL2 to the HRD1-SEL1L complex to form an active retrotranslocation complex. The UBL domain of HERP1 has an additional DERL2-independent function in ERAD.\",\n      \"method\": \"siRNA double knockdown, co-immunoprecipitation, ubiquitination assay, retrotranslocation assay, pulse-chase degradation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple substrates, double KD, Co-IP, ubiquitination and retrotranslocation assays in single rigorous study\",\n      \"pmids\": [\"24366871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Herp depletion leads to upregulation of autophagy regulators Atg5 and Beclin-1 (the latter via reduced Hrd1-dependent proteasomal degradation), resulting in increased autophagic flux that clears poly-ubiquitin protein aggregates and protects cells from glucose starvation-induced death.\",\n      \"method\": \"Stable shRNA knockdown, LC3-II Western blot, GFP-LC3 puncta assay, protein aggregation assay, cell viability assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable KD with multiple autophagy readouts and mechanistic explanation, single lab\",\n      \"pmids\": [\"24120520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"gp78 (an ER E3 ubiquitin ligase) together with Ube2g2 mediates polyubiquitylation of HERP, driven by a physical interaction between the CUE domain of gp78 and the UBL domain of HERP, leading to proteasomal degradation of HERP during ER stress recovery.\",\n      \"method\": \"In vitro ubiquitylation assay, co-immunoprecipitation, domain interaction mapping (CUE-UBL), siRNA knockdown, pulse-chase assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitylation plus domain-level interaction mapping and in vivo validation\",\n      \"pmids\": [\"24496447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nrf1 transcription factor directly activates Herpud1 expression during ER stress through antioxidant response elements in the Herpud1 promoter; loss of Nrf1 decreases Herpud1 expression and abolishes its ER stress induction.\",\n      \"method\": \"Nrf1 knockout cells, chromatin immunoprecipitation (ChIP), transactivation reporter assays, liver tissue analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct binding, KO cells, and transactivation assays provide convergent evidence\",\n      \"pmids\": [\"25637874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HERPUD1 protects against oxidative stress-induced apoptosis by downregulating IP3 receptor (ITPR)-mediated Ca2+ release from the ER; HERPUD1 knockdown increases cytosolic and mitochondrial Ca2+ and cell death, which is abolished by ITPR antagonism or intracellular Ca2+ chelation.\",\n      \"method\": \"Stable shRNA knockdown, flow cytometry (cell death), Ca2+ imaging (cytosolic and mitochondrial), ITPR pharmacological inhibition, BAPTA-AM chelation\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with Ca2+ imaging and pharmacological rescue, single lab\",\n      \"pmids\": [\"26616647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HERP interacts with TBK1 (TANK-binding kinase 1) and amplifies MAVS signaling, facilitating phosphorylation and nuclear translocation of IRF3 and NF-κB to enhance type-I and type-III IFN expression and inhibit RNA virus replication. HERP induction by EV71 is dependent on MAVS.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays for IFN promoters, phosphorylation assays, nuclear translocation by immunofluorescence, siRNA knockdown, virus replication assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and multiple downstream signaling readouts in single lab\",\n      \"pmids\": [\"28954889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Herpud1 knockout mice develop cardiac hypertrophy and dysfunction; Herpud1 deficiency elevates IP3R protein levels and increases cytosolic and nuclear Ca2+ in cardiomyocytes. Herpud1 negatively regulates cardiac hypertrophy by promoting IP3R degradation via the ERAD pathway.\",\n      \"method\": \"Herpud1 knockout mouse model, echocardiography, siRNA knockdown in cardiomyocytes, IP3R Western blot, Ca2+ imaging, hypertrophic marker expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout combined with in vitro KD, multiple orthogonal readouts (IP3R levels, Ca2+, hypertrophic markers)\",\n      \"pmids\": [\"29042597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HERPUD1 is required for osteoblast differentiation and mineralization; its expression increases as differentiation progresses with activation of ERAD and proteasomal degradation. HERPUD1 absence blocks mineralization and reduces alkaline phosphatase activity, while overexpression activates the osteoblast differentiation program.\",\n      \"method\": \"siRNA knockdown, overexpression in MC3T3-E1 and primary osteoblasts, alkaline phosphatase activity assay, calcium deposit measurement, Runx2/osterix expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with multiple differentiation readouts, single lab\",\n      \"pmids\": [\"29570393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRKCSH (glucosidase II beta subunit) interacts with HERP and inhibits HERP-mediated ubiquitination of TRPP2/polycystin-2, thereby protecting TRPP2 from ERAD; PRKCSH co-localizes with TRPP2 in the ER and binds TRPP2's C-terminal domain.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, zebrafish overexpression/depletion, co-localization by immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro ubiquitination inhibition, and zebrafish epistasis, single lab\",\n      \"pmids\": [\"19801576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Homocysteine-induced epigenetic hypermethylation of the HERP promoter correlates with decreased HERP mRNA expression, and promoter CpG island methylation is sufficient to suppress Herp transcription. Acute homocysteine causes transient promoter demethylation and Herp induction; the AARE and CREB binding sites in the Herp promoter mediate homocysteine-induced transcription.\",\n      \"method\": \"Luciferase reporter assays with AARE/CREB site mutations, methylation-specific PCR, mRNA quantitative PCR in patient samples and cell lines\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of promoter elements combined with methylation analysis and expression data\",\n      \"pmids\": [\"17020760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hypoxia-induced p300 acetyltransferase interacts with and acetylates XBP1s, enhancing XBP1s stability and its transcriptional activation of Herpud1 through ERSE-II. The p300/XBP1s/Herpud1 axis promotes M2 macrophage polarization.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assay, ChIP/promoter reporter assay, siRNA knockdown, macrophage polarization assay, mouse laser-induced CNV model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, acetylation assay, and functional downstream readouts in single lab\",\n      \"pmids\": [\"34057287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HERPUD1 promotes ferroptosis sensitivity in liver cancer cells by reducing MDM2 ubiquitination of glutathione synthetase (GSS), leading to GSS ubiquitination/degradation and decreased glutathione (GSH) levels, thus increasing susceptibility to ferroptosis.\",\n      \"method\": \"Overexpression/knockdown, ubiquitination assay for GSS/MDM2 interaction, GSH measurement, ferroptosis sensitivity assay, mouse xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with in vivo validation, single lab\",\n      \"pmids\": [\"36038536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Herpud1 regulates insulin secretion in pancreatic beta cells; Herpud1 knockdown in DBA/2 islets reduces glucose-stimulated insulin secretion and decreases Nnt expression, while Herpud1 overexpression increases Nnt expression, placing Herpud1 upstream of Nnt in insulin secretion regulation.\",\n      \"method\": \"siRNA knockdown, Herpud1 overexpression in MIN6 cells and DBA/2 islets, glucose-stimulated insulin secretion assay, microarray profiling\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined functional readout, genetic epistasis with Nnt, single lab\",\n      \"pmids\": [\"23620059\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HERPUD1 (Herp/Mif1) is an ER-resident integral membrane protein with a cytoplasm-facing N-terminal ubiquitin-like domain (UBL) that is strongly induced by ER stress via multiple UPR branches (ATF6/XBP1, PERK/ATF4) and by transcription factors including Luman/CREB3 and Nrf1; it functions as a scaffolding hub of the ERAD multiprotein complex by directly binding the E3 ubiquitin ligase HRD1 and recruiting DERL2, p97, and ubiquilins to facilitate retrotranslocation and proteasomal degradation of misfolded ER proteins; it also maintains ER Ca2+ homeostasis by promoting ERAD-dependent degradation of IP3 receptors (limiting Ca2+ release to the cytosol and mitochondria); its own turnover is regulated by gp78/Ube2g2-mediated K48-linked ubiquitylation (through CUE domain–UBL domain interaction) and by POSH-mediated K63-linked ubiquitylation that controls its localization; and it plays roles in innate immune signaling by binding TBK1 to amplify MAVS/IRF3/NF-κB-dependent IFN production during viral infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HERPUD1 (Herp/Mif1) is an ER-resident integral membrane protein with a cytoplasm-facing N-terminal ubiquitin-like domain that serves as a stress-inducible scaffolding hub of the ER-associated degradation (ERAD) machinery [#0, #7]. It is among the most strongly induced targets of the unfolded protein response, regulated combinatorially through both the IRE1/XBP1 and ATF6 ER-stress branches and the shared PERK/eIF2\\u03b1/ATF4 branch [#4], and through additional transcription factors acting at its promoter elements, including Luman/CREB3 at ERSE-II and Nrf1 at antioxidant response elements [#8, #20]. Mechanistically, HERPUD1 assembles a high-molecular-mass ERAD complex by binding directly to the E3 ubiquitin ligase HRD1 and recruiting the retrotranslocation factors p97, Derlin/DERL2 and VIMP, and by engaging ubiquilins to deliver substrates to the 26S proteasome [#7, #9, #11, #17]. Its UBL domain is required for efficient HRD1-mediated ubiquitylation and degradation of lumenal substrates such as NHK \\u03b11-antitrypsin, and HERPUD1 compartmentalizes misfolded proteins and HRD1 within the ER quality control compartment, where it acts as a membrane-anchored shuttle analogous to hHR23 [#12, #16, #17]. Through ERAD-dependent turnover of ER Ca2+ release channels, principally IP3 receptors, HERPUD1 limits Ca2+ release to the cytosol and mitochondria, protecting cells against ER-stress- and oxidative-stress-induced apoptosis [#5, #14, #21]; loss of this function in vivo produces impaired glucose tolerance, ischemic vulnerability, and cardiac hypertrophy with elevated IP3R levels [#15, #23]. HERPUD1 is itself a short-lived protein whose UBL domain drives rapid proteasomal turnover, including gp78/Ube2g2-mediated K48-linked ubiquitylation during ER-stress recovery and POSH-mediated K63-linked ubiquitylation that governs its trafficking between the trans-Golgi network and ER upon Ca2+ perturbation [#3, #10, #19]. Beyond core ERAD, HERPUD1 binds TBK1 to amplify MAVS-dependent IRF3/NF-\\u03baB signaling and type-I/III interferon production during RNA virus infection [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the basic identity of HERPUD1 as a stress-inducible ER membrane protein, defining the molecular object before any function was known.\",\n      \"evidence\": \"Antibody detection, membrane topology assays and stress induction in cultured cells; promoter reporter assays mapping a functional ERSE\",\n      \"pmids\": [\"10922362\", \"10708769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic function of the UBL domain not yet defined\", \"No binding partners identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First physical interactions and a functional context were assigned, linking Herp to presenilins and amyloid processing.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression and A\\u03b2 ELISA in presenilin-dependent cells; ULD deletion mapping\",\n      \"pmids\": [\"11799129\", \"14550564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"UBL/ULD role in A\\u03b2 generation dissociated from degradation but mechanism unclear\", \"Single-lab Co-IP without reciprocal validation in independent systems\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how HERPUD1 is induced and showed it is cytoprotective during ER stress, connecting transcriptional control to a survival phenotype.\",\n      \"evidence\": \"Genetic epistasis across UPR branch mutants; RNAi, overexpression, Ca2+ imaging, caspase assays and knockout F9 cells\",\n      \"pmids\": [\"14742429\", \"15102845\", \"15147274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of Ca2+ stabilization not yet defined\", \"ERAD substrate spectrum not delineated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined HERPUD1 as a direct binding partner of HRD1 within a retrotranslocation complex, establishing its scaffolding role in ERAD.\",\n      \"evidence\": \"Reciprocal Co-IP, sucrose gradient sedimentation and pull-down assays\",\n      \"pmids\": [\"16289116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity of the complex not addressed\", \"Stoichiometry of HERP within the complex unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined substrate selectivity and the proteasome-linking function, and identified POSH-mediated K63 ubiquitylation controlling HERP localization.\",\n      \"evidence\": \"siRNA knockdown, reciprocal Co-IP, proteasome association and pulse-chase assays for BiP-substrate ERAD; in vitro ubiquitination and confocal localization for POSH\",\n      \"pmids\": [\"18042451\", \"17420289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why HERP serves nonglycosylated/BiP but not calnexin substrates unresolved\", \"Trigger linking Ca2+ perturbation to POSH ubiquitylation not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified Luman/CREB3 as a direct transcriptional activator at ERSE-II, expanding the regulatory inputs beyond the canonical UPR triad.\",\n      \"evidence\": \"ChIP, promoter mutagenesis, siRNA knockdown and luciferase reporter assays\",\n      \"pmids\": [\"16940180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Luman versus ATF6/XBP1/ATF4 in vivo unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed ubiquilin recruitment by HERP is the link delivering specific substrates to the proteasome, mechanistically connecting scaffold to degradation.\",\n      \"evidence\": \"Co-IP, ubiquilin siRNA knockdown and transmembrane-deletion mutant rescue with pulse-chase degradation\",\n      \"pmids\": [\"18307982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate subset requiring ubiquilins not fully mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established UBL-domain-dependent regulation of HRD1 ubiquitylation and HERP's role in degrading ER Ca2+ release channels, unifying ERAD scaffolding with Ca2+ homeostasis.\",\n      \"evidence\": \"UBL mutagenesis, ubiquitylation and pulse-chase assays for NHK; KD, UBL deletion, proteasome inhibition, Ca2+ imaging and A53T-\\u03b1Syn transgenic mice for IP3R/RyR turnover\",\n      \"pmids\": [\"21149444\", \"22045699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HERP selects channel substrates not defined\", \"Direct versus indirect role in channel ubiquitylation not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined HERPUD1's spatial role in the ERQC, its redundancy with HERP2, and a DERL2-recruitment mechanism, refining the architecture of the active retrotranslocation complex.\",\n      \"evidence\": \"Immunofluorescence/co-localization with KD; double siRNA knockdown, Co-IP, ubiquitination and retrotranslocation assays across multiple substrates\",\n      \"pmids\": [\"24478453\", \"24366871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the membrane-anchored hub is predictive only\", \"DERL2-independent UBL function not mechanistically explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the CUE-UBL interaction driving gp78/Ube2g2-mediated K48 ubiquitylation, explaining HERP's own rapid turnover during stress recovery.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution, domain-interaction mapping, siRNA and pulse-chase\",\n      \"pmids\": [\"24496447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between gp78-driven and POSH-driven ubiquitylation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended HERPUD1 function beyond ERAD into innate immunity and into in vivo cardiac physiology, broadening its biological scope.\",\n      \"evidence\": \"Co-IP, IFN reporter, phosphorylation and nuclear translocation assays with virus replication for TBK1/MAVS; knockout mice, echocardiography, KD, IP3R Western and Ca2+ imaging for cardiac hypertrophy\",\n      \"pmids\": [\"28954889\", \"29042597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus scaffold-mediated role in TBK1 signaling unclear\", \"Single-lab evidence for the immune axis\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated HERPUD1 in non-canonical contexts including ferroptosis, osteoblast differentiation, autophagy and metabolic regulation, indicating context-dependent roles.\",\n      \"evidence\": \"Knockdown/overexpression with ubiquitination, GSH and ferroptosis assays; differentiation, autophagy flux, and insulin-secretion readouts across separate studies\",\n      \"pmids\": [\"36038536\", \"29570393\", \"24120520\", \"23620059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these phenotypes depend on the core ERAD/Ca2+ functions not resolved\", \"Each context characterized in a single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HERPUD1's substrate selection, its self-turnover by competing ubiquitin ligases, and its diverse non-ERAD activities are mechanistically integrated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of the membrane-anchored HERP-HRD1 complex\", \"Rules governing substrate channeling to ubiquilins versus DERL2 undefined\", \"Mechanistic link between Ca2+ regulation and the immune/metabolic roles unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 9, 16, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 14, 17]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 7, 16]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 9, 12, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [\"HRD1-SEL1L ERAD complex\"],\n    \"partners\": [\"HRD1\", \"DERL2\", \"p97/VCP\", \"VIMP\", \"POSH\", \"gp78\", \"UBQLN\", \"TBK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}