HERPUD1 Human
Description
ER Stress Response and Protein Quality Control
HERPUD1 is upregulated during ER stress and regulates the unfolded protein response (UPR) and ERAD pathways . It:
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Ubiquitinates misfolded proteins: Targets substrates for proteasomal degradation via its ULD .
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Modulates ERAD components: Interacts with Hrd1 (E3 ligase) and UBQLN1/2 (ubiquitin receptors) .
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Maintains calcium homeostasis: Regulates IP3R (inositol 1,4,5-trisphosphate receptor) degradation, impacting cytosolic Ca²⁺ levels .
Cellular Stress Adaptation
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Autophagy modulation: Stabilized HERPUD1 (via UBL domain deletion or S59D mutation) reduces autophagy and promotes ER-lysosome membrane contact sites (MCS), enhancing stress survival .
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Ferroptosis regulation: Upregulation by corosolic acid sensitizes liver cancer cells to ferroptosis by reducing glutathione synthesis .
Cardiac Hypertrophy and Dysfunction
HERPUD1 knockout in mice leads to:
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Hypertrophy: Elevated IP3R levels, increased cytosolic/nuclear Ca²⁺, and activation of pro-hypertrophic pathways .
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Dysfunction: Reduced fractional shortening (FS), ejection fraction (EF), and mitochondrial OCR .
| Parameter | HERPUD1-KO Mice | Wild-Type Mice |
|---|---|---|
| FS (%) | ↓↓ (20–30% reduction) | Normal |
| EF (%) | ↓↓ (15–25% reduction) | Normal |
| IP3R Protein Levels | ↑↑ (2–3-fold increase) | Basal |
Cancer and Ferroptosis
In liver cancer cells:
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HERPUD1 upregulation by corosolic acid reduces glutathione synthetase (GSS) expression, lowering GSH levels and enhancing ferroptosis sensitivity .
Transcriptional Control
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Nrf1-dependent induction: ER stress activates Nrf1, which binds ARE-like elements in the HERPUD1 promoter .
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ER stress markers: CHOP, BiP, and XBP1 are co-regulated with HERPUD1 .
Protein Interactome
Key interactors identified via BioGRID :
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ERAD components: Hrd1, Derlin-1, Sel1L.
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Chaperones: GRP94, Calnexin.
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Signaling proteins: Presenilins, UBQLN1/2.
Therapeutic Potential
| Disease | Mechanism | Outcome |
|---|---|---|
| Cardiac Hypertrophy | ↓ HERPUD1 → ↑ IP3R → ↑ Ca²⁺ → Hypertrophy | Targeting HERPUD1 may mitigate stress |
| Liver Cancer | ↑ HERPUD1 + Ferroptosis inducer → ↓ GSH → Ferroptosis | Enhanced tumor sensitivity |
| Neurodegeneration | HERPUD1 overexpression → ↑ Amyloid-β → Neurotoxicity | Requires caution in Alzheimer’s |
Experimental Models
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Knockout mice: Reveal cardiac dysfunction and ER stress exacerbation .
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siRNA knockdown: Demonstrates autophagy suppression and ER-lysosome remodeling .
Expression Patterns
HERPUD1 is highly expressed in:
Product Specs
Product Science Overview
The HERPUD1 gene is located on chromosome 16 in humans . The protein encoded by this gene contains an N-terminal ubiquitin-like domain, which is essential for its interaction with the ER-associated degradation (ERAD) system . This system is responsible for the ubiquitination and subsequent degradation of misfolded proteins in the ER .
HERPUD1 is an early marker of ER stress and is involved in the unfolded protein response (UPR) . The UPR aims to restore normal function by halting protein translation, degrading misfolded proteins, and activating signaling pathways that lead to increased production of molecular chaperones involved in protein folding . HERPUD1 is also implicated in the regulation of calcium ion homeostasis within the ER .
HERPUD1 has been associated with several diseases, including hereditary breast ovarian cancer syndrome . Its role in tumorigenesis, particularly in ovarian cancer, has been studied, revealing that HERPUD1 promotes cancer cell survival by sustaining autophagy . This suggests that HERPUD1 could be a potential target for therapeutic interventions in cancer treatment .
Recombinant HERPUD1 refers to the protein produced through recombinant DNA technology, which allows for the expression of the HERPUD1 protein in various host cells. This technology is crucial for studying the protein’s function and for developing potential therapeutic applications.
