Trends in Neurosciences
ReviewBalancing act: deubiquitinating enzymes in the nervous system
Section snippets
Ubiquitin and the nervous system
The development and function of the nervous system depends on cellular processes ranging from DNA transcription to protein degradation and on conserved signaling pathways between and within cells. These diverse processes and pathways rely on key regulatory elements that dictate the āwhenā and the āhowā of neuronal development, function and disease. One such element is the post-translational conjugation of ubiquitin (Ub) (see Glossary) to proteins. An evolutionarily conserved 8.5 kDa protein
Deubiquitinating enzymes and the nervous system
The human genome encodes approximately 95 potential DUBs [18], categorized into five classes based on homologies within the catalytic domains (Figure 1). Many DUBs contain additional non-catalytic domains that mediate binding to poly-Ub chains with specific linkages, to specific substrates or to functional protein partners [14]. By performing one or more of the proteolytic functions summarized in Figure 2, DUBs modulate various cellular pathways including cell growth [e.g. BRCA1 associated
DUBs as therapeutic targets
The ubiquitin-proteasome system (UPS) has long been an attractive therapeutic target owing to its important role in protein quality control and the regulation of other cellular pathways. Currently, the proteasome inhibitor Bortezomib (VelcadeĀ®) is used to treat cancers including multiple myeloma and mantle cell lymphoma [65]. However, proteasome inhibition has undesirable side effects owing to the fact that its indiscriminate inhibition affects all cellular processes that normally rely on
Concluding remarks
The development and integrity of the nervous system depend on the close regulation of numerous Ub-dependent pathways by specific DUBs (Table 1). Balanced ubiquitination/deubiquitination and continued availability of mono-Ub are important for synapse structure and function. Specific DUBs that are currently known to play a role at the synapse include UCHL1, USP14 and Faf/USP9X. In addition to ensuring that mono-Ub is available at the synapse, DUBs probably control the turnover of specific
Acknowledgments
We thank Drs Roger Albin, K. Matthew Scaglione, Karin List, Izabela Podgorski, Julie Boerner and Michael Bannon for critical reading of this manuscript. We regret that space restrictions prevent us from discussing all of the published reports on DUBs in the nervous system. This work was supported by National Institutes of Health (NIH) grants to S.V.T. (NS064097) and H.L.P. (NS038712, AG034228).
Glossary
- Ataxia
- gross lack of coordination. A neurological symptom that usually indicates a dysfunction of neural pathways involved in motor coordination.
- Deubiquitinating enzymes (DUBs)
- a family of cysteine and metallo-proteases that cleave chemical bonds between ubiquitin molecules or between ubiquitin and another protein.
- K48-linked ubiquitin chains
- ubiquitināubiquitin linkages that generally target substrate proteins for degradation by the proteasome.
- K63-linked ubiquitin chains
- ubiquitin-ubiquitin
References (105)
Ubiquitin is a component of neurofibrillary tangles in a variety of neurodegenerative diseases
Neurosci. Lett.
(1988)A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin
Neurosci. Lett.
(1988)Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia
Cell
(1997)A genomic and functional inventory of deubiquitinating enzymes
Cell
(2005)- et al.
The functions of UCH-L1 and its relation to neurodegenerative diseases
Neurochem. Int.
(2007) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory
Cell
(2006)Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant
Neurochem. Int.
(2007)Either part of a Drosophila epsin protein, divided after the ENTH domain, functions in endocytosis of delta in the developing eye
Curr. Biol.
(2003)Conserved roles for Slit and Robo proteins in midline commissural axon guidance
Neuron
(2004)- et al.
Polyglutamine neurodegeneration: protein misfolding revisited
Trends Neurosci.
(2008)
The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits K63-linkages in mixed linkage ubiquitin chains
J. Biol. Chem.
Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination
Biochem. Biophys. Res. Commun.
Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism
Mol. Cell
Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes
J. Biol. Chem.
ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology
Cell
Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening
Neurochem. Int.
Defining the human deubiquitinating enzyme interaction landscape
Cell
N-terminal ubiquitination: more protein substrates join in
Trends Cell Biol.
The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity
Mol. Cell
Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages
J. Biol. Chem.
Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities
Cell
Crystal structure and solution NMR studies of Lys48-linked tetraubiquitin at neutral pH
J. Mol. Biol.
Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling
J. Biol. Chem.
K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage specific antibody
Mol. Cell
Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice
Am. J. Pathol.
USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product
Mol. Cell Neurosci.
Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain
Ann. Neurol.
Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease
J. Pathol.
Ubiquitin is a component of paired helical filaments in Alzheimer's disease
Science
Persistent activation of cAMP-dependent protein kinase by regulated proteolysis suggests a neuron-specific function of the ubiquitin system in Aplysia
J. Neurosci.
Control of cell fate by a deubiquitinating enzyme encoded by the fat facets gene
Science
Ubiquitination-dependent mechanisms regulate synaptic growth and function
Nature
Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease
Nat. Genet.
Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice
Nat. Genet.
CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1
Nat. Genet.
Enhancement of proteasome activity by a small-molecule inhibitor of USP14
Nature
Protein partners of deubiquitinating enzymes
Biochem. J.
To ubiquitinate or to deubiquitinate: it all depends on the partners
Biochem. Soc. Trans.
Breaking the chains: structure and function of the deubiquitinases
Nat. Rev. Mol. Cell Biol.
Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes
Annu. Rev. Biochem.
Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes
Mol. Cell Prot.
Emerging roles for ubiquitin and protein degradation in neuronal function
Pharmacol. Rev.
Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases
Biochemistry
Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron
Hum. Mol. Genet.
Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1
J. Neurosci.
Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease
Proc. Natl. Acad. Sci. U.S.A.
Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction
Proc. Natl. Acad. Sci. U.S.A.
The ubiquitin pathway in Parkinson's disease
Nature
Pathogenic mutations in Parkinson disease
Hum. Mutat.
Transgenic rescue of ataxia mice with neuronal-specific expression of ubiquitin-specific protease 14
J. Neurosci.
Cited by (112)
Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons
2022, American Journal of Human GeneticsRedox regulation of DUBs and its therapeutic implications in cancer
2021, Redox BiologyCrystal structure of the Thr316Ala mutant of a yeast JAMM deubiquitinase: Implication of active-site loop dynamics in catalysis
2021, Acta Crystallographica Section F: Structural Biology CommunicationsDeubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity
2023, Cell Biology and Toxicology