HERPUD1 — Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1

HERPUD1 — Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HERPUD1 — Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HERPUD1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>16q13</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>9709</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>607340</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000128604</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5X5</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>ERAD component / UPR regulator</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~46 kDa</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">SEL1L</td>
<td>ERAD component</td>
</tr>
<tr>
<td class="label">HRD1</td>
<td>E3 ligase</td>
</tr>
<tr>
<td class="label">VCP/p97</td>
<td>AAA ATPase</td>
</tr>
<tr>
<td class="label">IRE1</td>
<td>UPR regulator</td>
</tr>
<tr>
<td class="label">ATF6</td>
<td>UPR transcription factor</td>
</tr>
<tr>
<td class="label">PERK</

HERPUD1 — Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HERPUD1 — Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HERPUD1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>16q13</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>9709</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>607340</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000128604</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5X5</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>ERAD component / UPR regulator</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~46 kDa</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">SEL1L</td>
<td>ERAD component</td>
</tr>
<tr>
<td class="label">HRD1</td>
<td>E3 ligase</td>
</tr>
<tr>
<td class="label">VCP/p97</td>
<td>AAA ATPase</td>
</tr>
<tr>
<td class="label">IRE1</td>
<td>UPR regulator</td>
</tr>
<tr>
<td class="label">ATF6</td>
<td>UPR transcription factor</td>
</tr>
<tr>
<td class="label">PERK</td>
<td>UPR kinase</td>
</tr>
<tr>
<td class="label">VDAC1</td>
<td>Mitochondrial channel</td>
</tr>
<tr>
<td class="label">IP3R</td>
<td>Calcium channel</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

HERPUD1 (Homocysteine-Responsive Endoplasmic Reticulum-Resident Ubiquitin-Like Domain Protein 1), also known as HERPUD1 or Kes1, is a critical ER membrane protein involved in ER-associated degradation (ERAD) and the unfolded protein response (UPR). It plays essential roles in protein quality control, ER stress response, calcium homeostasis, and mitochondrial function. HERPUD1 is implicated in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and hereditary spastic paraplegia (HSP), where ER stress is a prominent pathological feature[@sarras2010][@hoozemans2012].

Gene Overview

Molecular Function

ER-Associated Degradation (ERAD)

HERPUD1 is a central component of the ERAD pathway, which retrotranslocates misfolded proteins from the ER lumen to the cytoplasm for ubiquitin-proteasome degradation[@koksal2015][@okumura2015]:

• Substrate recognition: HERPUD1 recognizes misfolded proteins in the ER lumen and membrane
• Retrotranslocation: Forms a channel allowing protein export to the cytosol
• Ubiquitination: Recruits E3 ubiquitin ligases (e.g., Hrd1, gp78) to the retrotranslocation site
• Proteasomal delivery: Targets ubiquitinated substrates to the 26S proteasome

Unfolded Protein Response (UPR)

HERPUD1 regulates the three major UPR branches[@heiser2012]:

Through these mechanisms, HERPUD1 coordinates the adaptive response to ER stress, promoting cellular survival or triggering apoptosis when stress is irremediable.

Calcium Homeostasis

HERPUD1 plays important roles in ER calcium regulation:

• Modulates ER calcium store release
• Regulates store-operated calcium entry (SOCE)
• Links ER calcium dynamics to mitochondrial function
• Protects against calcium-induced cell death

ER-Mitochondria Contact Sites

HERPUD1 localizes to ER-mitochondria contact sites (ERMCS)[@yang2022]:

• Regulates calcium transfer between ER and mitochondria
• Influences mitochondrial membrane potential
• Affects apoptosis signaling
• Contributes to mitophagy regulation

Expression Pattern

HERPUD1 shows tissue-specific expression with high levels in metabolically active tissues[@segain2014]:

• Brain: Highest expression in cerebral cortex and hippocampus
• Pancreas: Very high expression in pancreatic β-cells (insulin-producing)
• Liver: Hepatocytes show robust expression
• Kidney: Renal tubular cells
• Muscle: Skeletal muscle fibers
• Neuronal expression: Both neurons and astrocytes; elevated in AD and PD brains

Role in Neurodegenerative Diseases

Alzheimer's Disease

HERPUD1 is strongly implicated in AD pathogenesis through multiple mechanisms[@hoozemans2012][@chen2016][@xu2023]:

ER Stress Response

• HERPUD1 is upregulated in AD brains, particularly in neurons surrounding amyloid plaques
• Chronic ER stress in AD activates HERPUD1 as part of the protective UPR
• The intensity of HERPUD1 expression correlates with disease severity
• HERPUD1 polymorphisms affect AD susceptibility

APP Processing

• HERPUD1 influences amyloid precursor protein (APP) processing
• Altered HERPUD1 affects β- and γ-secretase activity
• ER stress modulation affects amyloid-beta production

Protein Homeostasis

• HERPUD1 helps clear misfolded proteins that accumulate in AD
• Tau pathology affects HERPUD1 localization and function
• Dysregulated ERAD contributes to protein aggregate formation

Parkinson's Disease

HERPUD1 is implicated in PD through its role in ER stress and alpha-synuclein clearance[@yan2016]:

Alpha-Synuclein Toxicity

• HERPUD1 expression is altered in PD models and brains
• Overexpression of HERPUD1 protects against alpha-synuclein toxicity
• ER stress induced by alpha-synuclein activates HERPUD1
• Impaired ERAD leads to accumulation of toxic protein species

ER-Mitochondria Dysfunction

• PD-associated mutations affect ER-mitochondria contact sites
• HERPUD1 deficiency disrupts calcium homeostasis in dopaminergic neurons
• Mitochondrial dysfunction in PD is exacerbated by HERPUD1 dysregulation

Dopaminergic Neuron Vulnerability

• ER stress is particularly toxic to dopaminergic neurons
• HERPUD1 provides neuroprotection through UPR regulation
• Loss of HERPUD1 function contributes to neuronal death

Hereditary Spastic Paraplegia (HSP)

Recessive mutations in HERPUD1 cause HSP type 31 (SPG31)[@belal2010]:

• Biallelic loss-of-function mutations
• Disrupted ERAD leads to ER stress in corticospinal neurons
• Axonal degeneration through ER dysfunction
• Variable phenotype with onset in adolescence or early adulthood
• Additional features may include peripheral neuropathy

Amyotrophic Lateral Sclerosis

• ER stress is a major pathological feature in ALS
• HERPUD1 expression is altered in motor neurons
• TDP-43 pathology affects ER quality control
• HERPUD1 dysfunction may contribute to protein aggregate accumulation

Therapeutic Implications

Targeting HERPUD1 presents therapeutic opportunities for neurodegenerative diseases[@onishi2016][@wang2020][@chen2023][@park2024]:

ER Stress Modulators

• Small molecule ER stress modulators: Enhance HERPUD1 expression and function
• UPR inhibitors: Targeting specific branches to promote neuroprotection
• ER chaperone inducers: Increase overall ER folding capacity

Gene Therapy Approaches

• HERPUD1 overexpression: AAV-mediated delivery to increase ERAD capacity
• CRISPR activation: Upregulate endogenous HERPUD1 expression
• Variant-specific correction: For HSP-causing mutations

Combination Strategies

• HERPUD1 plus autophagy enhancers
• ER stress modulators plus mitochondrial protectants
• Anti-alpha-synuclein plus ERAD enhancement

Interacting Proteins and Pathways

Direct Protein Interactions

Pathway Membership

• ERAD pathway
• Unfolded protein response
• ER-mitochondria contact sites
• Calcium signaling
• Autophagy-lysosome pathway
• Apoptosis signaling

Animal Models

Mouse Models

• HERPUD1 knockout: Viable but shows increased sensitivity to ER stress
• Transgenic overexpression: Protected against ER stress-induced neurodegeneration
• Conditioned knockout: Neuron-specific deletion causes progressive neurodegeneration

In Vitro Models

• Primary neurons: Cortical, dopaminergic, motor neurons
• iPSC-derived neurons: Patient-specific models for AD, PD, and HSP
• SH-SY5Y: Dopaminergic neuronal model

Clinical Considerations

Genetic Testing

• HERPUD1 sequencing available for HSP diagnosis
• Genetic counseling recommended for families with SPG31
• Variant interpretation is established for known pathogenic mutations

Biomarkers

• HERPUD1 expression in peripheral blood mononuclear cells
• CSF ER stress markers
• Imaging for ER dysfunction (experimental)

See Also

• [ER Stress Pathway](/mechanisms/er-stress-unfolded-protein-response)
• [ERAD Pathway](/mechanisms/erad-pathway)
• [Unfolded Protein Response](/entities/unfolded-protein-response)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia)
• [Alpha-Synuclein](/proteins/alpha-synuclein)
• [APP Protein](/proteins/app-protein)
• [Tau Protein](/proteins/tau-protein)

External Links

• [NCBI Gene: HERPUD1](https://www.ncbi.nlm.nih.gov/gene/9709)
• [OMIM: HERPUD1](https://www.omim.org/entry/607340)
• [UniProt: HERPUD1](https://www.uniprot.org/uniprot/Q9Y5X5)
• [Ensembl: HERPUD1](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000128604)