Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy. Recruitment of CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is blocked by pre-treatment with tatCN21, a CaMKII inhibitor, at a concentration that inhibits the translocation of CaMKII to the PSD. Furthermore, CaMKII co-immunoprecipitates with CYLD from solubilized PSD fractions, indicating an association between the proteins. Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. Activation of CaMKII in isolated PSDs promotes phosphorylation of CYLD on the same residues and also enhances endogenous deubiquitinase activity specific for K63-linked polyubiquitins. Since K63-linked polyubiquitin conjugation to proteins inhibits their interaction with proteasomes, CaMKII-mediated recruitment and upregulation of CYLD is expected to remove K63-linked polyubiquitins and facilitate proteasomal degradation at the PSD.
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PMID:CaMKII mediates recruitment and activation of the deubiquitinase CYLD at the postsynaptic density. 2461 25

Ubiquitination-directed proteasomal degradation of synaptic proteins, presumably mediated by lysine 48 (K48) of ubiquitin, is a key mechanism in synapse and neural circuit remodeling. However, more than half of polyubiquitin (polyUb) species in the mammalian brain are estimated to be non-K48; among them, the most abundant is Lys 63 (K63)-linked polyUb chains that do not tag substrates for degradation but rather modify their properties and activity. Virtually nothing is known about the role of these nonproteolytic polyUb chains at the synapse. Here we report that K63-polyUb chains play a significant role in postsynaptic protein scaffolding and synaptic strength and plasticity. We found that the postsynaptic scaffold PSD-95 (postsynaptic density protein 95) undergoes K63 polyubiquitination, which markedly modifies PSD-95's scaffolding potentials, enables its synaptic targeting, and promotes synapse maturation and efficacy. TNF receptor-associated factor 6 (TRAF6) is identified as a direct E3 ligase for PSD-95, which, together with the E2 complex Ubc13/Uev1a, assembles K63-chains on PSD-95. In contrast, CYLD (cylindromatosis tumor-suppressor protein), a K63-specific deubiquitinase enriched in postsynaptic densities, cleaves K63-chains from PSD-95. We found that neuronal activity exerts potent control of global and synaptic K63-polyUb levels and, through NMDA receptors, drives rapid, CYLD-mediated PSD-95 deubiquitination, mobilizing and depleting PSD-95 from synapses. Silencing CYLD in hippocampal neurons abolishes NMDA-induced chemical long-term depression. Our results unveil a previously unsuspected role for nonproteolytic polyUb chains in the synapse and illustrate a mechanism by which a PSD-associated K63-linkage-specific ubiquitin machinery acts on a major postsynaptic scaffold to regulate synapse organization, function, and plasticity.
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PMID:Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity. 2897 54

Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA (GRIA1-4) receptor expression without affecting the levels of NMDA (GRIN) or GABAA receptors. Ubiquitin over-expression also negatively impacted hippocampus-dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA3-CA1 synapses. These changes occurred in a dose-dependent manner in that mice with the highest levels of ubiquitin over-expression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress-induced changes observed in neurological disorders.
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PMID:Chronic over-expression of ubiquitin impairs learning, reduces synaptic plasticity, and enhances GRIA receptor turnover in mice. 3045 Dec 89