Gene[ITCH](/entities/itch)
UniProt[Q9Y5K6](https://www.uniprot.org/uniprot/Q9Y5K6)
PDB Structures4NDD, 5C91, 6QNR
Molecular Weight903,982 Da
Subcellular LocalizationCytoplasm, Nucleus, Endoplasmic reticulum
Protein FamilyHECT-type E3 ubiquitin ligase, NEDD4 family
ITCH (Itchy Homolog, E3 Ubiquitin Protein Ligase) is a HECT-type E3 ubiquitin ligase belonging to the NEDD4 family. It plays critical roles in protein quality control, signal transduction, and immune regulation. ITCH-mediated ubiquitination targets proteins for degradation via the ubiquitin-proteasome system and regulates various cellular processes relevant to neurodegeneration.
ITCH contains an N-terminal C2 domain for calcium-dependent membrane localization, multiple WW domains for protein-protein interactions, and a C-terminal HECT domain that catalyzes ubiquitin transfer. The WW domains recognize PY motifs (PPxY) in substrate proteins, enabling substrate specificity.
¶ Domain Architecture
- C2 Domain (1-150): Calcium-dependent phospholipid binding, membrane targeting
- WW Domain 1 (172-205): Protein-protein interaction, PY motif binding
- WW Domain 2 (214-247): Protein-protein interaction, PY motif binding
- WW Domain 3 (258-291): Protein-protein interaction, PY motif binding
- WW Domain 4 (328-361): Protein-protein interaction, PY motif binding
- HECT Domain (450-903): Ubiquitin ligase catalytic activity
In the nervous system, ITCH regulates:
- Synaptic plasticity: Controls AMPA receptor trafficking and synaptic strength
- Protein quality control: Targets misfolded proteins for degradation
- Signal transduction: Modulates MAPK/ERK and PI3K/Akt pathways
- Inflammatory responses: Regulates NF-κB signaling in microglia
- Autophagy: Participates in selective autophagy receptor degradation
ITCH functions as a molecular scaffold assembling signaling complexes and as an E3 ligase mediating substrate ubiquitination.
ITCH dysfunction contributes to AD pathogenesis through multiple mechanisms:
- Aβ metabolism: ITCH regulates APP processing and Aβ generation via ubiquitination of BACE1 and ADAM10
- Tau pathology: ITCH-mediated degradation of tau kinases (GSK-3β) may influence tau phosphorylation
- Synaptic dysfunction: Loss of ITCH leads to impaired synaptic plasticity and memory deficits
- Neuroinflammation: ITCH regulates microglial activation and cytokine production
- α-Synuclein degradation: ITCH contributes to selective autophagy of α-synuclein aggregates
- Mitochondrial quality control: ITCH regulates mitophagy through PINK1/Parkin-independent pathways
- Dopaminergic neuron survival: ITCH protects against oxidative stress-induced death
- TDP-43 pathology: ITCH may regulate TDP-43 ubiquitination and clearance
- Protein aggregation: ITCH dysfunction contributes to ubiquitin-proteasome system impairment
- Axonal transport: ITCH regulates transport protein degradation
- Mutant huntingtin clearance: ITCH promotes degradation of toxic HTT fragments
- Transcriptional regulation: ITCH modulates transcription factor activity altered in HD
ITCH represents a potential therapeutic target:
- ITCH agonists could enhance clearance of toxic proteins (Aβ, α-syn, mutant HTT)
- Small molecule activators are under development for protein aggregation disorders
- ITCH antagonists may have utility in certain inflammatory conditions
- WW domain blockers could modulate ITCH-substrate interactions
- ITCH knockout mice show spontaneous colitis and behavioral abnormalities
- shRNA/siRNA knockdown vectors for experimental use
- Recombinant ITCH protein for biochemical assays
- Galligan et al., ITCH deficiency in neurodegeneration (2022)
- Zhang et al., ITCH and Alzheimer's disease pathogenesis (2021)
- Chen et al., ITCH-mediated mitophagy in Parkinson's disease (2023)
- Sanchez et al., HECT E3 ligases in protein aggregation disorders (2020)
- Wang et al., ITCH regulates synaptic plasticity (2021)