HERC2 Gene

HERC2 Gene

Overview

HERC2 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HERC2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HERC2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q13.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>8924</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>607318</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000128731</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q9Y5K5</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>HERC family (HECT-type E3 ubiquitin ligases)</td>
</tr>
<tr>
<td class="label">Length</td>
<td>4,834 amino acids</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Function</td>
</tr>
<tr>
<td class="label">p53</td>
<td>Tumor suppressor</td>
</tr>
<tr>
<td class="label">TPR</td>
<td>Nuclear pore</td>
</tr>
<tr>
<td class="label">RNFs</td>
<td>E3 ligases</td>
</tr>
<tr>
<td class="label">RNA Pol II</td>
<td>Transcription</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Small molecule activators</td>
<td>HECT domain</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>HERC2 delivery</td>
</tr>
<tr>
<td class="label">Autophagy enhancers</td>
<td>mTOR pathway</td>
</tr>
<tr>
<td class="label">DNA repair promoters</td>
<td>ATM/ATR</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/hepatocellular-carcinoma" style="color:#ef9a9a">Hepatocellular Carcinoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">11 edges</a></td>
</tr>
</table>

HERC2 (HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2) is one of the largest E3 ubiquitin ligases in humans, with critical functions in DNA damage response, protein quality control, autophagy, and lysosomal function. As a member of the HERC family, HERC2 contains a unique combination of HECT (Homologous to E6AP C-terminus) domain and RLD (RCC1-like domain) domains, enabling it to participate in diverse cellular processes["@cruz2020"]. Dysregulation of HERC2 has been implicated in various neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, as well as neurodevelopmental disorders such as Angelman syndrome and Joubert syndrome.

Gene Information

Molecular Function

E3 Ubiquitin Ligase Activity

HERC2 functions as an E3 ubiquitin ligase, catalyzing the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. The protein contains:

• HECT domain (~350 aa at C-terminus): Catalytic domain that forms a thioester intermediate with ubiquitin before transfer to substrates
• RLD domains (x3): RCC1-like domains that mediate protein-protein interactions and may function as guanine nucleotide exchange factors
• N-terminal region: Contains multiple protein interaction motifs

Substrate Specificity

HERC2 has been shown to ubiquitinate numerous substrates:

• p53: Tumor suppressor protein; HERC2-mediated ubiquitination regulates p53 stability and activity
• TPR (Nuclear pore complex protein): Involved in nuclear export
• MARCHF proteins: Other E3 ligases
• RNA polymerase II subunits: Regulation of transcription

DNA Damage Response

HERC2 plays a critical role in the cellular response to DNA damage[@kelley2021]. Key functions include:

• Checkpoint activation: HERC2 helps activate DNA damage checkpoint kinases
• Repair recruitment: Mediates recruitment of repair proteins to damage sites
• Chromatin remodeling: Facilitates chromatin changes required for repair
• Telomere maintenance: HERC2 is involved in telomere length regulation and protection

Role in Protein Quality Control

Ubiquitin-Proteasome System

HERC2 contributes to the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system), the primary pathway for targeted protein degradation in cells[@hanpude2019]. Key functions include:

• Misfolded protein clearance: HERC2 helps tag misfolded and damaged proteins for degradation
• Quality control checkpoint: Participates in surveillance mechanisms that identify compromised proteins
• Aggregation prevention: By promoting degradation of aggregation-prone proteins, HERC2 prevents toxic aggregate formation

Autophagy Regulation

HERC2 also regulates [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration), the major degradative pathway for bulk cytoplasm, protein aggregates, and organelles[@yang2023]:

• mTOR signaling modulation: HERC2 influences mTORC1 activity, a central regulator of autophagy
• Lysosomal function: HERC2 affects lysosomal biogenesis and function
• Selective autophagy: May contribute to selective autophagy of specific substrates
• Vesicle trafficking: Involved in autophagy-related vesicle movement

Role in Neurodegeneration

Alzheimer's Disease

In Alzheimer's disease (AD), HERC2 dysfunction contributes to pathogenesis through multiple mechanisms:

Parkinson's Disease

HERC2 alterations in Parkinson's disease (PD) include:

• Alpha-synuclein quality control: HERC2-mediated ubiquitination may affect alpha-synuclein aggregation
• Mitophagy: HERC2's role in selective autophagy is relevant to mitochondrial dysfunction in PD
• Lysosomal function: HERC2 regulates autophagy-lysosome pathway integrity, which is critical for PD pathogenesis

Neurodevelopmental Disorders

HERC2 mutations cause several neurodevelopmental disorders:

The overlap between developmental and degenerative mechanisms suggests that HERC2 function is crucial throughout life.

Protein Structure and Domains

HERC2 is one of the largest human proteins, containing multiple functional domains:

N-terminus → [RLD1] → [RLD2] → [RLD3] → [HECT domain] ← C-terminus

• RLD1-3: RCC1-like domains (each ~150 aa), involved in protein interactions
• HECT domain: ~350 aa catalytic domain with E3 ubiquitin ligase activity
• Linker regions: Low-complexity regions potentially involved in regulatory interactions

Expression Patterns

Brain Expression

HERC2 shows high expression in the brain:

• Cerebral cortex: Highest expression in pyramidal neurons
• Hippocampus: Particularly in CA1 and CA3 regions
• Cerebellum: Purkinje cells show strong expression
• Subventricular zone: Neural progenitor cell populations

Cell Type Expression

Within the brain, HERC2 is expressed in:

• Neurons: Both excitatory and inhibitory neurons
• Astrocytes: Glial cells
• Microglia: Immune cells of the brain
• Oligodendrocytes: Myelin-producing cells

HERC2 in Neurodegeneration

Alzheimer's Disease

In Alzheimer's disease (AD), HERC2 dysfunction contributes to pathogenesis through multiple mechanisms:

Parkinson's Disease

HERC2 alterations in Parkinson's disease (PD) include:

• Alpha-synuclein quality control: HERC2-mediated ubiquitination may affect alpha-synuclein aggregation
• Mitophagy: HERC2's role in selective autophagy is relevant to mitochondrial dysfunction in PD
• Lysosomal function: HERC2 regulates autophagy-lysosome pathway integrity, which is critical for PD pathogenesis

Amyotrophic Lateral Sclerosis

In ALS:

• HERC2 mutations affect protein quality control in motor neurons
• DNA damage accumulation contributes to motor neuron death
• Autophagy dysfunction exacerbates protein aggregation

Huntington's Disease

• Mutant huntingtin clearance impaired with HERC2 dysfunction
• DNA repair deficits worsen with age
• Autophagy-lysosome pathway compromised

HERC2 and Protein Quality Control

Ubiquitin-Proteasome System

HERC2 contributes to the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system), the primary pathway for targeted protein degradation in cells[@hanpude2019]. Key functions include:

• Misfolded protein clearance: HERC2 helps tag misfolded and damaged proteins for degradation
• Quality control checkpoint: Participates in surveillance mechanisms that identify compromised proteins
• Aggregation prevention: By promoting degradation of aggregation-prone proteins, HERC2 prevents toxic aggregate formation

Autophagy Regulation

HERC2 also regulates [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration), the major degradative pathway for bulk cytoplasm, protein aggregates, and organelles[@yang2023]:

• mTOR signaling modulation: HERC2 influences mTORC1 activity, a central regulator of autophagy
• Lysosomal function: HERC2 affects lysosomal biogenesis and function
• Selective autophagy: May contribute to selective autophagy of specific substrates
• Vesicle trafficking: Involved in autophagy-related vesicle movement

HERC2 and DNA Damage Response

Cellular Response to DNA Damage

HERC2 plays a critical role in the cellular response to DNA damage[@kelley2021]. Key functions include:

• Checkpoint activation: HERC2 helps activate DNA damage checkpoint kinases
• Repair recruitment: Mediates recruitment of repair proteins to damage sites
• Chromatin remodeling: Facilitates chromatin changes required for repair
• Telomere maintenance: HERC2 is involved in telomere length regulation and protection

DNA Damage in Neurons

Neurons are particularly vulnerable to DNA damage:

• Oxidative DNA damage: High metabolic rate leads to ROS production
• Limited repair capacity: Post-mitotic neurons have reduced DNA repair
• Age-related accumulation: DNA damage accumulates with aging
• Neurodegeneration: DNA damage triggers neuronal death pathways

HERC2 and Cellular Stress

Oxidative Stress

HERC2 responds to oxidative stress:

• Nrf2 pathway: Links to antioxidant response
• Protein oxidation: Helps clear oxidatively damaged proteins
• Mitochondrial stress: Affected by mitochondrial dysfunction

ER Stress

Endoplasmic reticulum stress:

• Unfolded protein response: HERC2 in protein quality control
• Calcium homeostasis: Related to ER function
• Apoptosis: ER stress-induced cell death pathways

Proteostasis Network

HERC2 interacts with:

• Chaperone systems: Hsp70, Hsp90 networks
• Autophagy receptors: p62, OPTN
• Ubiquitin chains: Different linkage types for different fates

HERC2 in Specific Brain Regions

Hippocampus

In the hippocampus:

• High HERC2 in CA1 and CA3 pyramidal neurons
• Role in memory formation and consolidation
• Age-related changes in HERC2 expression
• Relevance to hippocampal dysfunction in AD

Cerebral Cortex

In the cortex:

• Layer-specific expression patterns
• Excitatory neurons show highest expression
• Dysfunction in cortical atrophy
• Implications for cognitive decline

Cerebellum

In the cerebellum:

• Purkinje cells: High HERC2 expression
• Motor coordination functions
• Ataxia and cerebellar degeneration links

HERC2 Variants and Mutations

Disease-Causing Variants

Neurodegeneration Risk Variants

• Common variants may influence AD/PD risk
• Rare variants with incomplete penetrance
• Polygenic contribution to disease risk

HERC2 and Neuroinflammation

Microglial HERC2

In microglia:

• Regulates inflammatory responses
• Affects phagocytosis of protein aggregates
• Cytokine release modulation
• Role in neuroinflammation

Astrocyte HERC2

In astrocytes:

• Protein quality control functions
• Response to brain injury
• Contribution to neuroinflammation

Therapeutic Strategies

Small Molecule Approaches

• Ubiquitin system modulators: Enhance HERC2 function
• Autophagy inducers: Bypass HERC2 dysfunction in autophagy
• DNA damage repair enhancers: Address DNA damage accumulation

Gene Therapy

• Functional HERC2 delivery: Restore protein function
• Allele-specific approaches: For Angelman syndrome
• RNAi knock-down: For dominant-negative variants

Combination Therapies

• UPS modulators + autophagy enhancers
• DNA repair + protein clearance
• Gene therapy + small molecules

Animal Models

Mouse Models

• HERC2 knockout: Lethal in embryonic stage
• Conditional knockout: Brain-specific deletion
• Transgenic models: Human variant expression

Phenotypic Findings

• Learning and memory deficits
• Accelerated aging phenotypes
• Protein aggregation
• DNA damage accumulation

Research Methods

Protein Interaction Studies

• Co-immunoprecipitation
• Mass spectrometry
• Yeast two-hybrid screening

Functional Assays

• Ubiquitination assays
• Autophagy flux measurements
• DNA damage repair kinetics

Animal Studies

• Behavioral testing
• Histopathology
• Biochemical analysis

Clinical Relevance

Biomarkers

• HERC2 expression in peripheral blood
• HERC2 variants as genetic risk factors
• Protein levels in CSF

Clinical Testing

• Genetic testing for variants
• Protein expression analysis
• Functional assays

HERC2 and Metabolic Dysfunction

Metabolic Syndrome and Neurodegeneration

HERC2 connects metabolic dysfunction to neurodegeneration:

Mitochondrial Function

• Energy metabolism: HERC2 affects mitochondrial ATP production
• Oxidative phosphorylation: Complex I-V components
• Mitochondrial dynamics: Fusion and fission regulation

HERC2 and Synaptic Function

Synaptic Plasticity

HERC2 regulates synaptic function:

• Postsynaptic density: Composition and function
• Synaptic vesicle cycling: Regulates neurotransmitter release
• Dendritic spine morphology: Spine shape and number

Synapse Dysfunction in Disease

• Early synapse loss: Precedes neuronal death in AD
• Excitotoxicity: Glutamate-induced damage
• Synaptic pruning: Aberrant in neurodegeneration

HERC2 Substrate Specificity

Known Substrates

Substrate Discovery

• Proteomics approaches
• Ubiquitin-profiling
• Interaction databases

HERC2 Structure-Function

Domain Architecture

N-terminus → [RLD1] → [RLD2] → [RLD3] → [HECT domain] ← C-terminus

• RLD1-3: RCC1-like domains (each ~150 aa), involved in protein interactions
• HECT domain: ~350 aa catalytic domain with E3 ubiquitin ligase activity
• Linker regions: Low-complexity regions potentially involved in regulatory interactions

Catalytic Mechanism

HERC2 in Cellular Senescence

Senescence-Associated Changes

• Senescence-associated secretory phenotype (SASP): HERC2 in inflammatory responses
• Cellular aging markers: p16, p21 regulation
• DNA damage accumulation: Enhanced in senescence

Implications for Neurodegeneration

• Senescent neurons in AD/PD brains
• Non-cell autonomous toxicity
• Therapeutic target for senescence clearance

HERC2 and Blood-Brain Barrier

BBB Function

• Endothelial tight junctions
• Pericyte coverage
• Transport regulation

BBB Dysfunction in Disease

• Increased permeability in neurodegeneration
• Transport of toxins and immune cells
• Therapeutic delivery challenges

HERC2 in Neurodevelopmental Disorders

Angelman Syndrome

• Maternal allele mutations cause disease
• Imprinting mechanism
• UBE3A-ATS transcript regulation

Joubert Syndrome

• Cerebellar and brainstem malformations
• Molar tooth sign on MRI
• HERC2 as causative gene

Intellectual Disability

• Non-syndromic forms
• Synaptic function implications
• Cognitive assessment findings

HERC2 and Aging

Age-Related Changes

• Declining HERC2 expression
• Accumulating DNA damage
• Reduced protein quality control

Interventions

• Caloric restriction effects
• Exercise benefits
• Pharmacological approaches

Clinical Trials and Therapeutics

Current Landscape

• No HERC2-specific trials for neurodegeneration
• Broader ubiquitin system targeting
• Gene therapy approaches in development

Therapeutic Strategies

Research Methods

Protein Interaction Studies

• Co-immunoprecipitation
• Mass spectrometry
• Yeast two-hybrid screening

Functional Assays

• Ubiquitination assays
• Autophagy flux measurements
• DNA damage repair kinetics

Animal Studies

• Behavioral testing
• Histopathology
• Biochemical analysis

Biomarkers and Diagnostics

Genetic Testing

• Targeted panel testing
• Whole exome sequencing
• Copy number analysis

Protein Biomarkers

• HERC2 in cerebrospinal fluid
• Blood-based markers
• Imaging correlates

See Also

• [E3 Ubiquitin Ligases in Neurodegeneration](/mechanisms/ubiquitin-ligases-neurodegeneration)
• [Autophagy-Lysosome Pathway](/mechanisms/autophagy-lysosome-pathway)
• [Protein Aggregation Mechanisms](/mechanisms/protein-aggregation)
• [DNA Repair and Brain Aging](/mechanisms/dna-repair-neurodegeneration)
• [Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system)
• [Protein Quality Control](/mechanisms/protein-quality-control-network)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Angelman Syndrome](/diseases/angelman-syndrome)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving HERC2 Gene discovered through SciDEX knowledge graph analysis: