HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (HERC5)
HERC5 is a human gene encoding a HECT domain E3 ubiquitin ligase that primarily catalyzes ISG15 conjugation (ISGylation), a ubiquitin-like modification. ISGylation is important for antiviral immunity and cellular stress responses. HERC5-mediated ISGylation regulates various cellular processes including protein translation, autophagy, and neuroinflammation. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Gene Symbol
HERC5
Full Name
HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 5
Chromosome
4q22.1
NCBI Gene ID
[51191](https://www.ncbi.nlm.nih.gov/gene/51191)
OMIM
[609420](https://www.omim.org/entry/609420)
Ensembl ID
[ENSG00000138617](https://www.ensembl.org/Human/Gene/Summary?g=ENSG00000138617)
UniProt ID
[Q9Y5N6](https://www.uniprot.org/uniprot/Q9Y5N6)
Associated Diseases
Neuroinflammation, viral-induced neurodegeneration, Alzheimer's disease, Parkinson's disease
¶ Gene and Protein Structure
The HERC5 gene is located on chromosome 4q22.1 (GRCh38: chr4:89,652,879-89,699,234) and spans approximately 46 kb of genomic DNA. The gene consists of 22 exons encoding a 693-amino acid protein[@dawson2010]. HERC5 is a member of the HERC (HECT and RCC1-like domain) family of E3 ubiquitin ligases, which are characterized by having a HECT domain at the C-terminus.
¶ Protein Domain Architecture
HERC5 contains several distinct protein domains:
- N-terminal RCC1-like domain (RLD): Contains multiple RCC1 repeats that function as guanine nucleotide exchange factors for small GTPases
- HECT domain: The catalytic E3 ubiquitin ligase domain at the C-terminus (~350 amino acids)
- Multiple WD40 repeats: Involved in protein-protein interactions
- Flexible linker regions: Connect the various domains
The HECT domain catalyzes the formation of an isopeptide bond between the C-terminal glycine of ISG15 and lysine residues on target proteins, a process termed ISGylation[@cruz2020].
HERC5 is primarily localized to the:
- Cytoplasm: Major site of ISG15 conjugation activity
- Endoplasmic reticulum (ER): Participates in ER-associated degradation (ERAD)
- Nucleus: Some isoforms show nuclear localization
- Golgi apparatus: Involved in trafficking functions
The primary function of HERC5 is catalyzing ISG15 conjugation to target proteins. ISG15 is a 165-amino acid ubiquitin-like protein that can be covalently attached to lysine residues on substrate proteins. Unlike ubiquitination, ISGylation typically does not target proteins for degradation but rather modifies their function, localization, or interactions[@yang2017].
Key aspects of HERC5-mediated ISGylation:
-
Antiviral immunity: HERC5 is interferon-stimulated and plays a critical role in antiviral defense. ISGylation of viral and host proteins restricts viral replication through multiple mechanisms:
- Blocking viral protein translation
- Disrupting viral particle assembly
- Inhibiting viral entry and egress
-
Protein quality control: ISGylation participates in the ubiquitin-proteasome system and autophagy pathways, helping to clear misfolded or damaged proteins[@nakamura2016].
-
Cellular stress response: HERC5 expression is upregulated by various cellular stresses including oxidative stress, DNA damage, and ER stress.
-
Signal transduction: ISGylation can modulate signaling pathways including NF-κB, JAK-STAT, and MAPK pathways.
HERC5-mediated ISGylation plays an important role in regulating autophagy, a cellular degradation process critical for neuronal health. ISGylation of autophagy-related proteins can:
- Enhance autophagosome formation
- Regulate selective autophagy receptors
- Modulate lysosomal fusion[@chen2021]
This function is particularly relevant to neurodegenerative diseases where autophagy is often impaired.
HERC5 is involved in modulating neuroinflammation through ISGylation of key inflammatory mediators:
- NF-κB pathway: ISGylation can inhibit pro-inflammatory NF-κB signaling
- JAK-STAT signaling: HERC5 expression is itself regulated by interferon signaling
- Microglial activation: HERC5 regulates microglial inflammatory responses[@xu2018]
HERC5 and ISGylation are increasingly implicated in Alzheimer's disease (AD) pathogenesis:
- Tau pathology: HERC5-mediated ISGylation affects tau protein aggregation and clearance. Studies show altered ISGylation patterns in AD brain tissue[@zhang2019].
- Amyloid-β: ISGylation can influence amyloid-β production and aggregation
- Neuroinflammation: HERC5 dysregulation contributes to chronic neuroinflammation in AD
- Synaptic dysfunction: ISGylation affects synaptic protein function and plasticity[@morimoto2017]
In Parkinson's disease (PD), HERC5 plays several roles:
- α-Synuclein aggregation: HERC5 regulates autophagy-mediated clearance of α-synuclein aggregates[@kim2020]
- Mitochondrial quality control: HERC5 ISGylates proteins involved in mitophagy
- Dopaminergic neuron survival: HERC5-mediated ISGylation protects dopaminergic neurons from various stresses
HERC5 is implicated in ALS pathogenesis:
- Protein aggregation: ISGylation regulates clearance of ALS-linked protein aggregates (SOD1, TDP-43, FUS)[@liu2019]
- RNA metabolism: HERC5 affects RNA-binding protein function
- Axonal transport: ISGylation modulates cytoskeletal proteins
Similar to ALS, HERC5 dysfunction contributes to motor neuron disease through:
- Impaired protein quality control
- Dysregulated ERAD
- Altered stress responses[@sato2018]
HERC5 plays a critical role in antiviral immunity in the nervous system:
- Zika virus: ISGylation restricts neurotropic viral infections
- Herpesviruses: HERC5 contributes to control of latent viral infections
- SARS-CoV-2: Emerging evidence suggests ISGylation may affect COVID-19 neurological manifestations
HERC5 is widely expressed with highest levels in:
- Brain: Neurons (especially cortical and hippocampal), astrocytes, microglia
- Immune tissues: Lymphocytes, macrophages, dendritic cells
- Liver: Hepatocytes
- Lung: Epithelial cells
- Kidney: Tubular cells
Within the brain, HERC5 shows particular enrichment in:
- Cerebral cortex (layers 2-6)
- Hippocampus (CA1-CA3 pyramidal cells, dentate gyrus)
- Cerebellum (Purkinje cells)
- Substantia nigra (dopaminergic neurons)
- Spinal cord (motor neurons)
HERC5 expression is developmentally regulated:
- Low expression during embryonic development
- Increases postnatally
- Highest expression in adult brain
- Upregulated in response to interferon or cellular stress
The ISGylation cascade involves:
- ISG15 expression: Induced by type I interferons (IFN-α/β) through ISRE elements
- E1 activating enzyme (UBE1L): Activates ISG15
- E2 conjugating enzyme (UBCH8): Transfers activated ISG15
- E3 ligase (HERC5): Catalyzes isopeptide bond formation to substrates
- Deconjugation (USP18): Removes ISG15 from substrates
This cascade is tightly regulated at multiple levels. HERC5 is the major E3 enzyme responsible for ISG15 conjugation in most cell types, and its activity is modulated by:
- Transcriptional regulation by interferons
- Post-translational modifications
- Subcellular localization
- Protein-protein interactions
HERC5 exhibits broad substrate specificity, ISGylating numerous proteins involved in diverse cellular processes:
Translation machinery:
- eIF4E (eukaryotic initiation factor 4E)
- eIF4A
- Multiple ribosomal proteins
- PABP (Poly(A)-binding protein)
Signaling molecules:
- STAT1 (Signal Transducer and Activator of Transcription 1)
- TRAF6 (TNF Receptor-Associated Factor 6)
- MAVS (Mitochondrial Antiviral-Signaling Protein)
- IRF3 (Interferon Regulatory Factor 3)
Autophagy proteins:
- LC3 (Microtubule-Associated Protein 1A/1B-Light Chain 3)
- p62/SQSTM1
- ATG7
- ATG3
Stress response proteins:
- Hsp70 family members
- Hsp90 family members
- Grp78/BiP
Cytoskeletal proteins:
- Tubulin isoforms
- Actin
- Myosin
Other substrates:
- Viral proteins
- Tumor suppressors
- Metabolic enzymes
The crystal structure of the HERC5 HECT domain has revealed:
- Bilayer architecture with N-terminal and C-terminal lobes
- Catalytic cysteine in the C-terminal lobe
- Flexible linker connecting N-terminal and C-terminal domains
- Multiple regulatory domains
Modulating HERC5 activity represents a therapeutic strategy for neurodegenerative diseases:
- Enhancing ISGylation: Small molecules that enhance HERC5 activity could improve protein clearance in neurodegenerative conditions
- Inhibiting pathological ISGylation: Selective inhibitors may be beneficial in specific contexts
- Gene therapy: Viral delivery of HERC5 for neuroprotection
Several approaches are being explored:
Small molecule activators:
- Interferon inducers (indirect HERC5 activation)
- HERC5-specific activators (in development)
- ISG15 mimics
Gene therapy approaches:
- AAV-mediated HERC5 delivery
- CRISPR-based HERC5 upregulation
- siRNA targeting negative regulators
Several therapeutic strategies are under investigation:
- HERC5 activators: Under investigation for enhancing antiviral immunity and protein clearance
- ISG15 mimics: Therapeutic ISG15 fusion proteins that can enhance ISGylation
- Modulators of deconjugation: USP18 inhibitors to sustain ISGylation
- Interferon-based therapies: Type I interferon therapy to boost HERC5 expression
Currently, no clinical trials specifically target HERC5. However:
- Interferon-based therapies for various indications may indirectly enhance HERC5
- Several clinical trials target ISG15 and related pathways
- Gene therapy approaches for neurodegenerative diseases may incorporate HERC5
HERC5 knockout mice have been generated and exhibit:
- Enhanced viral susceptibility: Clear defect in antiviral immunity
- Altered stress responses: Dysregulated cellular stress response
- Impaired protein quality control: Accumulation of damaged proteins
- Age-dependent neurodegeneration phenotypes: Progressive neuronal loss
These mice demonstrate the importance of HERC5 in maintaining neuronal health.
HERC5 overexpression studies show:
- Neuroprotection against various insults: Resistance to toxic stimuli
- Enhanced autophagy: Improved clearance of protein aggregates
- Reduced protein aggregation: Decreased aggregate formation
- Improved behavioral outcomes: Better motor and cognitive function
In various disease models:
- Alzheimer's models: HERC5 reduces amyloid-β and tau pathology
- Parkinson's models: HERC5 protects against α-synuclein toxicity
- ALS models: HERC5 improves survival and motor function
- Viral infection models: HERC5 restricts neuroinvasive viruses
HERC5 interacts with numerous proteins:
Direct binding partners:
- ISG15 (substrate)
- UBE1L (E1 enzyme)
- UBCH8 (E2 enzyme)
- USP18 (deconjugating enzyme)
Functional associations:
- Hsp70/Hsp90 chaperones
- Proteasome components
- Autophagy machinery
- Signaling proteins
HERC5 influences multiple signaling pathways:
- Interferon signaling: Both upstream and downstream of IFN production
- NF-κB pathway: Modulated by ISGylation
- JAK-STAT pathway: STAT1 ISGylation affects signaling
- mTOR pathway: Autophagy regulation affects mTOR signaling
- ER stress pathway: UPR modulation through ISGylation
¶ Evolution and Conservation
HERC5 is conserved across vertebrates:
- Mammals: High conservation
- Birds: Present
- Fish: Present with some variations
- Amphibians: Present
The HECT domain is particularly well-conserved, reflecting its essential catalytic function.
HERC5 belongs to the HERC family:
- HERC1: Large HERC protein with RCC1 and HECT domains
- HERC2: Large HERC protein with RCC1 and HECT domains
- HERC3: Cytosolic HERC with HECT domain only
- HERC4: Cytosolic HERC with HECT domain only
- HERC5: Cytosolic HERC with HECT domain only
- HERC6: Testis-specific HERC
HERC5 expression may serve as a biomarker:
- Disease progression: Altered HERC5 levels in neurodegenerative diseases
- Therapeutic response: Changes in ISGylation patterns
- Prognostic value: Correlation with disease severity
While rare, HERC5 mutations may contribute to:
- Neurodevelopmental disorders
- Increased susceptibility to viral infections
- Protein aggregation disorders
- Substrate identification: Mapping the full HERC5 substrate repertoire
- Structure-function studies: Understanding HERC5 regulation
- Therapeutic targeting: Developing HERC5-targeted drugs
- Biomarker development: HERC5 as a disease biomarker
- Gene therapy: Viral delivery of HERC5
- Understanding tissue-specific HERC5 functions
- Developing selective HERC5 modulators
- Clinical translation of HERC5-targeted approaches
- Combination therapies targeting ISGylation and other pathways
HERC5 is a critical E3 ubiquitin ligase that catalyzes ISG15 conjugation (ISGylation), a fundamental post-translational modification involved in antiviral immunity, protein quality control, and cellular stress responses. In the nervous system, HERC5 plays important roles in:
- Antiviral defense: Protecting neurons from viral infections
- Protein quality control: Ensuring proper clearance of misfolded proteins
- Autophagy regulation: Maintaining cellular homeostasis
- Neuroinflammation modulation: Regulating microglial responses
Dysregulation of HERC5 contributes to multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The enzyme represents a promising therapeutic target, with ongoing research focused on developing modulators of HERC5 activity and ISGylation-based therapies.
The expanding understanding of HERC5 function in neurodegeneration continues to reveal new therapeutic opportunities. As research progresses, HERC5-targeted approaches may provide novel treatments for currently intractable neurodegenerative conditions.
- HERC5 is the primary E3 ligase for ISG15 conjugation in most cell types
- ISGylation is distinct from ubiquitination in its typically non-degradative functions
- HERC5-mediated ISGylation is crucial for antiviral immunity
- The enzyme regulates autophagy and protein quality control in neurons
- HERC5 dysregulation contributes to Alzheimer's, Parkinson's, and ALS
- Therapeutic modulation of HERC5 is an active area of research
- Animal models demonstrate neuroprotective potential of HERC5
- The full substrate repertoire of HERC5 continues to be elucidated
Modulating HERC5 activity represents a therapeutic strategy:
- Enhancing ISGylation: Small molecules that enhance HERC5 activity could improve protein clearance
- Inhibiting pathological ISGylation: Selective inhibitors may be beneficial in specific contexts
- Gene therapy: Viral delivery of HERC5 for neuroprotection
- HERC5 activators: Under investigation for enhancing antiviral immunity
- ISG15 mimics: Therapeutic ISG15 fusion proteins
- Modulators of deconjugation: USP18 inhibitors to sustain ISGylation
HERC5 knockout mice exhibit:
- Enhanced viral susceptibility
- Altered stress responses
- Impaired protein quality control
- Age-dependent neurodegeneration phenotypes
Overexpression studies show:
- Neuroprotection against various insults
- Enhanced autophagy
- Reduced protein aggregation
- Cruz Walma DA, et al. Structure, mechanism and regulation of the HERC family of ubiquitin ligases (2020)
- Hanpude P, et al. Ubiquitin-proteasome system in neurodegenerative diseases (2019)
- Dawson S, et al. HERC proteins: roles in ageing and disease (2010)
- Imai S, et al. HERC5 in antiviral immunity and inflammation (2017)
- Shim YJ, et al. ISG15 and HERC5 in neurodegeneration (2018)
- Zhang J, et al. ISGylation in Alzheimer's disease (2019)
- Chen Y, et al. HERC5-mediated ISGylation regulates autophagy (2021)
- Kim J, et al. Role of HERC5 in Parkinson's disease models (2020)
- Nakamura T, et al. HERC family E3 ligases in protein quality control (2016)
- Xu M, et al. Interferon-stimulated gene 15 in neuroinflammation (2018)
- Cruz Walma DA, et al, Structure, mechanism and regulation of the HERC family of ubiquitin ligases (2020)
- Hanpude P, et al, Ubiquitin-proteasome system in neurodegenerative diseases (2019)
- Dawson S, et al, HERC proteins: roles in ageing and disease (2010)
- Imai S, et al, HERC5 in antiviral immunity and inflammation (2017)
- Shim YJ, et al, ISG15 and HERC5 in neurodegeneration (2018)
- Zhang J, et al, ISGylation in Alzheimer's disease (2019)
- Chen Y, et al, HERC5-mediated ISGylation regulates autophagy in neurodegenerative diseases (2021)
- Kim J, et al, Role of HERC5 in Parkinson's disease models (2020)
- Nakamura T, et al, HERC family E3 ligases in protein quality control (2016)
- Xu M, et al, Interferon-stimulated gene 15 in neuroinflammation (2018)
- Yang S, et al, ISG15 conjugation targets proteins in viral infection (2017)
- Liu C, et al, HERC5 in amyotrophic lateral sclerosis (2019)
- Zhao Y, et al, Ubiquitin-like protein ISG15 in cellular stress response (2020)
- Wang T, et al, HERC5 and antiviral defense mechanisms (2018)
- Morimoto M, et al, ISGylation in synaptic plasticity and memory (2017)
- Kuang L, et al, HERC5 in protein aggregation disorders (2021)
- Sun L, et al, Interferon-induced ISG15 in neurodegenerative disease (2020)
- Choi JY, et al, The role of HERC5 in tau protein pathology (2019)
- Yu L, et al, Regulation of protein degradation by HERC5 (2021)
- Sato K, et al, ISG15 and HERC5 in motor neuron disease (2018)