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FLASH GENE
Symbol UCHL1 contributors: mct/npt/pgu - updated : 11-04-2018
HGNC name ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
HGNC id 12513
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • ubiquitin carboxyl-terminal hydrolase domain
  • HOMOLOGY
    interspecies homolog to murine Uchl1
    Homologene
    FAMILY
  • ubiquitin carboxyl-terminal hydrolase family 1 (peptidase family C12)
  • CATEGORY enzyme , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleolus
    basic FUNCTION
  • having ubiquitin hydrolase and ligase activities
  • involved in proteasomal degradation, a critical process for neuronal health
  • significant role in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner
  • catalyzing its own deubiquitination in an intramolecular manner
  • functions in maintaining normal synaptic structure in hippocampal neurons
  • plays a role in regulating principal pathways involved in oncogenesis
  • de-ubiquitinating enzyme with important functions in recycling of ubiquitin
  • negatively regulates TNFalpha-mediated vascular smooth muscle cell proliferation via suppressing ERK activation
  • required for the maintenance of the structure and function of the neuromuscular junctions and the loss of normal activity may result in neurodegeneration in the peripheral nervous system
  • plays a critical role in the maintenance of normal neuromuscular synaptic transmission
  • essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development
  • has dual functions, such as hydrolase activity on the chemical bonds formed by the C-terminal Gly of Ub and dimerization-dependent ubiquitin ligase activity
  • HTRA2-mediated cleavage of UCHL1 may play important roles in regulating the fine balance between cell growth and cell death
  • UCHL1 and HTRA2 pair may play important roles in regulating the balance between cell death and cell survival
  • is a neuron-restricted protein that acts as a deubiquitinating enzyme, ubiquitin ligase or monoubiquitin stabilizer (PMId: 23064229)
  • neuron-specific de-ubiquitinating enzyme and plays an important role in ubiquitin turnover through its C-terminal hydrolytic activity
  • is a novel regulator of the kinase activities of CDKs
  • is involved in podocyte injury and proteinuria
  • de-ubiquitinating enzyme that cleaves ubiquitin at its carboxyl terminal
  • may delay Alzheimer progression by regulating APP degradation in a long-term fashion
  • CELLULAR PROCESS cell cycle
    nucleotide, transcription
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • potentially contributing to CDKN1B degradation via its interaction and nuclear translocation with COPS5 (JAB1)
  • degradation of SNCA
  • physically interacts with LAMP2
  • is a natural substrate for the serine protease HTRA2 in the apoptotic pathway
  • has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity
  • stabilizes focal adhesion signaling in the absence of adhesion, as assessed by reduced caspase-dependent cleavage of PTK2 following cell detachment and sustained activity of the AKT1 signaling pathway
  • UCHL1 is a novel interaction partner of both NCAM1 isoforms (NCAM140, NCAM180) that regulates their ubiquitination and intracellular trafficking
  • UCH1LAS regulates UCHL1 expression at a post-transcriptional level
  • is a key regulator of the dichotomy between MTOR and CRTC2 signaling
  • UCHL1, is the major regulator of neuronal ubiquitin homeostasis, and indirectly modulates the turnover of SLC6A5
  • physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity
  • UCHL1 interacts with APP and regulates Abeta production
  • cell & other
    REGULATION
    repressed by oestradiol
    Other mono-Ub may regulate the enzymatic functions of UCHL1
    ASSOCIATED DISORDERS
    corresponding disease(s) PARK5 , NDGOA , SPG79
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in non-small cell lung cancer
    tumoral     --low  
    in cervical tumor (by hypermethylation)
    constitutional     --low  
    in Huntington diseaseand Alzheimer disease, and in replaceable neurons of hippocampus and olfactory bulb
    constitutional     --over  
    robustly increased in spinal muscular atrophy (SMA) patient fibroblasts
    constitutional       loss of function
    defective UCHL1 function may be an early contributor to vulnerability of pancreatic beta-cells for protein misfolding and proteotoxicity, hallmark defects in islets of T2DM
    Susceptibility
  • to Parkinson disease
  • to Alzheimer disease (AD)
  • Variant & Polymorphism other
  • S18Y polymorphism influencing the variability in age-onset of Huntington disease
  • carbonyl modification and subsequent abnormal interactions of carbonyl-modified UCHL1 with multiple proteins, including tubulin, constitute one of the causes of sporadic Parkinson disease
  • not protective effect of the UCHL1 S18Y polymorphism against AD
  • Candidate gene
  • role of GFAP and UCHL1 as candidate biomarkers for pediatric traumatic brain injury (TBI)
  • Marker
  • reliable and potential biomarker of neuronal damage after acute neurologic insults, such as ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury
  • aberrant DNA methylation of HTATIP2 and UCHL1, may serve as a potential predictive biomarker for Cholangiocarcinoma (CCA)
  • Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    potential target for Parkinson-modifying therapies
    neurologyneurodegenerativealzheimer
    overexpression of UCHL1 may be a safe and effective disease-modifying strategy to treat AD
    miscelleaneousurinarychronic kidney disease
    NFKB1-UCH-L1 interaction could be a novel therapeutic strategy for the treatment of podocyte lesions and proteinuria
    ANIMAL & CELL MODELS
  • gracile axonal dystrophic mouse (gad) which arbors a deletion of Uchl1
  • pharmacological inhibition of Uchl1 exacerbates rather than ameliorates disease symptoms in a mouse model of SMA
  • Uchl1 knockout mice should serve as a useful model of gut aging