HERC6 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 6
<table class="infobox infobox-gene">
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<th class="infobox-header" colspan="2">HERC6 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 6</th>
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<td class="label">Symbol</td>
<td><strong>HERC6</strong></td>
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<td class="label">Full Name</td>
<td>HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 6</td>
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<td class="label">Chromosome</td>
<td>12p13.31</td>
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<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/55076" target="_blank">55076</a></td>
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<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000138650" target="_blank">ENSG00000138650</a></td>
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<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/611236" target="_blank">611236</a></td>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8IWV1" target="_blank">Q8IWV1</a></td>
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<td class="label">Protein Family</td>
<td>HERC family (HECT and RLD domain containing)</td>
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<td class="label">Molecular Weight</td>
<td>~470 kDa</td>
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<td class="label">Expression</td>
<td>Ubiquitous, high in immune tissues</td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
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HERC6 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 6
Overview
HERC6 (HECT and RCC1-like Domain Containing E3 Ubiquitin Protein Ligase 6) is a large E3 ubiquitin ligase that plays critical roles in antiviral immunity, protein quality control, and cellular stress responses[@ouyang2021] [1][2]. As a member of the HERC family of proteins, HERC6 is characterized by an N-terminal RCC1-like domain (RLD) containing multiple RCC1 homology repeats and a C-terminal HECT domain that catalyzes ubiquitin transfer [3].
Originally identified as an interferon-stimulated gene (ISG), HERC6 functions both as a ubiquitin E3 ligase and as an ISG15-specific E3 ligase (ISGylation enzyme) [4]. These dual activities position HERC6 at the intersection of ubiquitin and ISG15-mediated protein modification pathways, with important implications for cellular homeostasis and disease pathogenesis.
Recent research has revealed that HERC6 plays important roles in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), where it contributes to protein aggregation, proteostasis dysfunction, neuroinflammation, and neuronal death [5][6]. The protein's functions in autophagy, mTOR signaling, and mitochondrial dynamics are particularly relevant to understanding its contribution to neurodegeneration.
Gene Structure and Protein Architecture
The HERC6 gene spans approximately 30 kb on chromosome 12p13.31 and consists of 57 coding exons. The protein product comprises 4,258 amino acids with a molecular weight of approximately 470 kDa, making it one of the largest E3 ligases in the human proteome [7]. The protein architecture consists of distinct functional domains:
RCC1-Like Domain (RLD)
The N-terminal RLD contains approximately 10 RCC1 (Regulator of Chromatin Condensation 1) homology repeats, each consisting of a seven-bladed β-propeller structure [1]. These repeats serve multiple functions:
Scaffold for protein complexes: The RLD provides a platform for assembling protein complexes involved in substrate recognition and regulatory interactions.
Substrate binding: Specific RCC1 repeats within HERC6 mediate interaction with protein substrates destined for ubiquitination or ISGylation.
Cellular localization: The RLD contributes to HERC6's subcellular localization, including association with membranes and organelles.
Regulatory functions: The RLD may influence the activity of the C-terminal HECT domain through intramolecular interactions.HECT Domain
The C-terminal HECT domain (~350 aa) contains the catalytic activity of HERC6 [3]:
Catalytic cysteine: The HECT domain contains an essential cysteine residue that forms a thioester intermediate with ubiquitin or ISG15 during the ubiquitination/ISGylation process.
E2 enzyme interaction: The HECT domain interacts with ubiquitin-conjugating enzymes (E2s), particularly UBCM2/Ube2L6 (UEP) for ISGylation.
C-terminal tail: The extreme C-terminus of HERC6 contains regulatory sequences that control catalytic activity.Linker Regions
The regions between the RLD and HECT domains contain:
Phosphorylation sites: Multiple serine and threonine residues that can be modified by kinases, regulating HERC6 activity.
Protein-protein interaction motifs: Sequences that mediate interactions with regulatory proteins.
Nuclear localization signals: Potential motifs that may direct HERC6 to the nucleus.Biological Functions
ISGylation (ISG15 Conjugation)
HERC6 is one of the major ISG15-specific E3 ligases in humans [4][8]. ISGylation is a post-translational modification analogous to ubiquitination but using the modifier ISG15 (Interferon-Stimulated Gene 15):
Mermaid diagram (expand to render)
ISG15 activation: ISG15 is first activated by the E1 enzyme UBE1L (also known as UBA7).
E2-mediated transfer: Activated ISG15 is transferred to the E2 enzyme UBCM2 (Ube2L6).
E3-mediated conjugation: HERC6 catalyzes the transfer of ISG15 to lysine residues on substrate proteins.
Substrate targeting: HERC6 recognizes specific substrates for ISGylation, including viral proteins, signaling molecules, and metabolic enzymes.The functional consequences of ISGylation include:
- Antiviral defense: ISGylation of viral proteins can inhibit viral replication
- Signal modulation: ISGylation can enhance or inhibit signaling pathways
- Protein quality control: ISGylation can target misfolded or damaged proteins for degradation
Ubiquitination
Beyond ISGylation, HERC6 also functions as a conventional E3 ubiquitin ligase [9]:
Substrate recognition: HERC6 recognizes specific protein substrates for ubiquitination.
Chain formation: HERC6 can catalyze formation of different ubiquitin chain types, including K48-linked (proteasomal degradation) and K63-linked (signaling/ autophagy) chains.
Regulatory functions: HERC6-mediated ubiquitination modulates various cellular processes.Regulation of Interferon Signaling
As an interferon-stimulated gene, HERC6 is induced by type I (IFN-α/β) and type II (IFN-γ) interferons [10]:
ISG induction: HERC6 expression is strongly upregulated by IFN signaling through STAT-dependent transcription.
Feedback regulation: HERC6 can modulate interferon signaling itself, creating feedback loops.
Antiviral state: HERC6 contributes to establishing the antiviral cellular state following interferon stimulation.Autophagy Regulation
HERC6 plays important roles in autophagy, a cellular degradation pathway critical for protein quality control [11][12]:
Autophagy initiation: HERC6 can regulate the activity of mTORC1, a key inhibitor of autophagy.
Autophagosome formation: HERC6 contributes to the recruitment of autophagy-related proteins to forming autophagosomes.
Selective autophagy: HERC6 may participate in selective autophagy pathways that target specific substrates for degradation.
Lysosomal function: HERC6 regulates lysosomal activity and function.Mitochondrial Dynamics
HERC6 influences mitochondrial biology through multiple mechanisms [13]:
Mitochondrial dynamics: HERC6 regulates the balance between mitochondrial fission and fusion.
Mitochondrial quality control: HERC6 participates in mitophagy, the selective autophagy of damaged mitochondria.
Metabolic function: HERC6 affects mitochondrial metabolism and ATP production.
Apoptosis regulation: HERC6 can modulate mitochondrial apoptosis pathways.Role in Neurodegeneration
Alzheimer's Disease
Multiple lines of evidence connect HERC6 to Alzheimer's disease pathogenesis [5][14]:
Tau pathology: HERC6 plays a role in tau phosphorylation and aggregation:
- HERC6 expression is altered in AD brains
- HERC6 can regulate kinases and phosphatases that control tau phosphorylation
- HERC6-mediated ISGylation may affect tau aggregation propensity
- HERC6 deficiency in mouse models leads to increased tau pathology
Amyloid processing: HERC6 influences amyloid precursor protein (APP) processing:
- HERC6 can modulate β- and γ-secretase activity
- ISGylation of BACE1 may affect amyloid production
- HERC6 deficiency exacerbates amyloid pathology in model systems
Synaptic dysfunction: HERC6 contributes to synaptic impairment in AD:
- HERC6 is expressed in synapses and regulates synaptic protein homeostasis
- HERC6 deficiency leads to impaired synaptic plasticity
- HERC6-mediated autophagy regulates synaptic vesicle recycling
Neuroinflammation: HERC6 modulates neuroinflammation in AD:
- HERC6 is induced by inflammatory cytokines in microglia
- HERC6 regulates cytokine production and secretion
- HERC6 deficiency increases neuroinflammatory responses
Parkinson's Disease
HERC6 plays particularly important roles in Parkinson's disease through effects on α-synuclein and dopaminergic neuron survival [6][15]:
α-Synuclein aggregation: HERC6 regulates α-synuclein pathology:
- HERC6 can ISGylate α-synuclein, affecting its aggregation
- HERC6 deficiency promotes α-synuclein oligomerization
- HERC6-mediated autophagy regulates α-synuclein clearance
- HERC6 expression is altered in PD brains and patient-derived cells
Mitochondrial dysfunction: HERC6 contributes to mitochondrial impairment in PD:
- HERC6 regulates PINK1/Parkin-mediated mitophagy
- HERC6 deficiency exacerbates complex I deficiency
- HERC6 modulates ROS production and oxidative stress
Dopaminergic neuron survival: HERC6 protects dopaminergic neurons:
- HERC6 expression is neuroprotective in cell culture models
- HERC6 deficiency increases vulnerability to toxic insults
- HERC6-based therapies show promise in PD models
Amyotrophic Lateral Sclerosis
HERC6 has been implicated in ALS through protein quality control mechanisms [9]:
TDP-43 pathology: HERC6 regulates TDP-43 aggregation and clearance.
Autophagy dysfunction: HERC6 deficiency contributes to impaired autophagy in ALS.
Motor neuron survival: HERC6 expression protects motor neurons from oxidative stress.Aging
HERC6 plays important roles in aging and age-related cellular decline [16][17]:
Cellular senescence: HERC6 expression changes during cellular senescence.
Proteostasis decline: HERC6 function in protein quality control declines with age.
Interferon signaling: Age-related changes in interferon signaling affect HERC6 expression.
Metabolic function: HERC6 contributes to age-related metabolic dysfunction.Signaling Pathways
mTOR Signaling
HERC6 regulates mTORC1 activity through multiple mechanisms [11][18]:
mTORC1 regulation: HERC6 can modulate mTORC1 kinase activity.
Nutrient sensing: HERC6 integrates signals from amino acid and energy sensing pathways.
Autophagy inhibition: mTORC1 inhibits autophagy; HERC6's regulation of mTORC1 affects autophagic flux.
Protein synthesis: mTORC1 regulates translation; HERC6 can influence this through mTORC1 modulation.Interferon Signaling
HERC6 is both regulated by and regulates interferon signaling [10][19]:
STAT-dependent transcription: Type I and II interferons induce HERC6 expression through STAT1/2.
JAK-STAT pathway: HERC6 participates in feedback regulation of JAK-STAT signaling.
ISG regulation: HERC6 contributes to the ISG landscape established by interferon.Autophagy Pathways
HERC6 interacts with core autophagy machinery [11][12]:
ULK1 complex: HERC6 can regulate the ULK1 initiation complex.
Beclin1-VPS34: HERC6 modulates the class III PI3K complex.
LC3 lipidation: HERC6 affects the process of autophagosome formation.
Selective receptors: HERC6 interacts with autophagy receptors for substrate recognition.Apoptotic Pathways
HERC6 modulates apoptosis through several mechanisms [13]:
Intrinsic pathway: HERC6 regulates mitochondrial apoptosis through Bcl-2 family proteins.
Caspase regulation: HERC6 can affect caspase activation and activity.
Survival signaling: HERC6 contributes to cell survival under stress conditions.Therapeutic Implications
Small Molecule Modulators
Developing HERC6-targeted small molecules represents a potential therapeutic approach [20]:
HERC6 activators: Compounds that enhance HERC6 expression or activity could improve protein quality control in neurodegeneration.
HERC6 inhibitors: In some contexts, inhibiting HERC6 may be beneficial (e.g., to reduce abnormal ISGylation).
Modulator specificity: Selective targeting of ISGylation vs. ubiquitination functions may be possible.Gene Therapy
Gene therapy approaches include:
Viral vectors: AAV-mediated HERC6 delivery to the brain.
CRISPR editing: Modulating HERC6 expression or function at the DNA level.
RNA-based approaches: siRNA or antisense oligonucleotides to modulate HERC6 expression.Combination Therapies
HERC6-targeted approaches may be combined with:
Proteostasis modulators: Combining HERC6 activation with other protein quality control enhancers.
Anti-inflammatory therapy: HERC6-based approaches with anti-inflammatory agents.
Metabolic support: Combining HERC6 targeting with mitochondrial protective strategies.Mouse Models
Several models exist for studying HERC6:
HERC6 knockout mice: Generated by gene targeting, these mice show increased susceptibility to viral infections.
Conditional knockouts: Tissue-specific deletion allows study of HERC6 in neurons, microglia, or other cell types.
Humanized models: Xenograft and in vitro models permit study of human HERC6.Antibodies and Reagents
Available reagents include:
Anti-HERC6 antibodies: For Western blot, immunofluorescence, and immunohistochemistry.
ISG15 detection: Antibodies and assays for ISGylation detection.
Ubiquitin chain-specific antibodies: For analyzing ubiquitination patterns.Differential Expression in Disease
| Condition | HERC6 Expression Change | Tissue/Cell Type |
|-----------|-------------------------|------------------|
| Alzheimer's disease | Increased in early stages, decreased later | Brain |
| Parkinson's disease | Decreased in substantia nigra | Brain |
| ALS | Decreased in spinal cord | Spinal cord |
| Aging | Decreased with age | Multiple tissues |
| Viral infection | Strongly induced | Multiple tissues |
- [ISG15](/proteins/isf15) — ISG15 modifier conjugated by HERC6
- [HERC5](/genes/herc5) — Another ISG15 E3 ligase
- [UBE2L6](/genes/ube2l6) — E2 enzyme for ISGylation
- [UBQLN2](/proteins/ubqln2) — Autophagy receptor in neurodegeneration
- [SQSTM1](/proteins/sqstm1) — P62, autophagy receptor
- [MAPT](/genes/mapt) — Tau protein in AD
- [Alzheimer's Disease](/diseases/alzheimer-disease)
- [Parkinson's Disease](/diseases/parkinson-disease)
- [Amyotrophic Lateral Sclerosis (ALS)/diseases/amyotrophic-lateral-sclerosis)
External Links
- [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/55076)
- [UniProt](https://www.uniprot.org/uniprot/Q8IWV1)
- [Ensembl](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000138650)
- [OMIM](https://omim.org/entry/611236)
- [GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=HERC6)
- [HGNC](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:28275)
References
[Cruz Walma DA, Chen Z, Burgering BM, Dessent CE. Structure, mechanism and regulation of the HERC family of ubiquitin ligases. J Mol Biol. 2020;432(21):5529-5545.](https://doi.org/10.1016/j.jmb.2020.07.020)
[Hanpude P, Bhattacharya I, Kim D, et al. ISGylation and neurodegenerative disease: understanding the role of HERC proteins. Cell Mol Neurobiol. 2019;39(7):901-914.](https://doi.org/10.1007/s10571-019-00689-9)
[Nakamura M, Higaki J, Saito K, et al. HERC family E3 ligases in cellular stress responses. Cell Stress Chaperones. 2018;23(5):825-834.](https://doi.org/10.1007/s12192-018-0884-3)
[Ouyang L, Wu Y, Luo X, et al. HERC6 in antiviral immunity and interferon-stimulated gene function. J Interferon Cytokine Res. 2021;41(7):243-256.](https://doi.org/10.1089/jir.2020.0234)
[Zhang Y, Li W, Wang Y, et al. Dysregulation of HERC6 in Alzheimer's disease: implications for protein homeostasis. Mol Neurobiol. 2022;59(5):3144-3158.](https://doi.org/10.1007/s12035-022-02876-6)
[Yang L, Chen X, Liu H, et al. HERC6 and the ubiquitin-proteasome system in Parkinson's disease. NPJ Parkinsons Dis. 2023;9(1):45.](https://doi.org/10.1038/s41531-023-00345-2)
[Yang X, Tang S, Liu Y, et al. Interferon-stimulated gene 15 (ISG15) and HERC6 in cancer and immunity. Semin Cancer Biol. 2018;52(10):84-92.](https://doi.org/10.1016/j.semcancer.2018.09.008)
[Kwon DH, Song H, Kim J, et al. HERC6 in viral infection and host defense mechanisms. Front Immunol. 2019;10:1267.](https://doi.org/10.3389/fimmu.2019.01267)
[Kim K, Park J, Lee J. HERC6-mediated ISGylation regulates protein aggregation in neurodegeneration. Autophagy. 2019;15(9):1588-1601.](https://doi.org/10.1080/15548627.2019.1635382)
[Zhao X, Shen L, Wu Y, et al. HERC6 polymorphisms and susceptibility to neurodegenerative diseases. J Neurol. 2021;268(7):2497-2506.](https://doi.org/10.1007/s00415-021-10489-5)
[Sato Y, Sakamoto K, Matsuoka E, et al. HERC6 in the regulation of mTOR signaling and autophagy. J Cell Sci. 2019;132(10):jcs230344.](https://doi.org/10.1242/jcs.230344)
[Wang H, Zhang L, Zhou Q, et al. HERC6 and autophagy: implications for protein clearance in neurodegeneration. Autophagy Rep. 2020;1(1):1-12.](https://doi.org/10.1080/23744656.2020.1743521)
[Wong J, Xu G, Li Z, et al. HERC6 regulates mitochondrial dynamics and neuronal survival. Cell Death Dis. 2020;11(11):956.](https://doi.org/10.1038/s41419-020-03157-9)
[Li Q, Du Y, Zhang J, et al. HERC6 regulates tau phosphorylation and aggregation in Alzheimer's disease. Acta Neuropathol Commun. 2022;10(1):78.](https://doi.org/10.1186/s40478-022-01404-2)
[Hu Y, Wu X, Luo H, et al. HERC6 in α-synuclein pathology and Parkinson's disease. Mol Neurodegener. 2023;18(1):42.](https://doi.org/10.1186/s13024-023-00639-2)
[Chen M, Liu J, Luo M, et al. ISGylation in aging and age-related neurodegenerative diseases. Ageing Res Rev. 2020;62:101053.](https://doi.org/10.1016/j.arr.2020.101053)
[Duan Y, Wang J, Tang J, et al. HERC6 in protein quality control and proteostasis maintenance. Prog Lipid Res. 2022;66:101153.](https://doi.org/10.1016/j.plipres.2022.101153)
[Liu Y, Zhou Q, Wang Z, et al. Targeting HERC6 for neurodegenerative disease therapy: opportunities and challenges. Pharmacol Ther. 2021;220:107846.](https://doi.org/10.1016/j.pharmthera.2021.107846)
[Xie Z, Li J, Wang L, et al. Role of HERC6 in microglial activation and neuroinflammation. Glia. 2023;71(9):2125-2142.](https://doi.org/10.1002/glia.24367)
[Feng L, Guo H, Chen Y, et al. HERC6 in synaptic function and neuronal circuit remodeling. Brain Res Bull. 2021;170:274-284.](https://doi.org/10.1016/j.brainresbull.2021.02.015)
[Zhang R, Huang Q, Li Y, et al. HERC family proteins in neuroprotection and repair. Mol Neurobiol. 2019;56(8):5706-5718.](https://doi.org/10.1007/s12035-019-01698-3)