ArticleProceedings of the National Academy of Sciences of the United States of America2017
Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 54 citations in OpenAlex.
- CYLD-mediated lysine63 deubiquitination regulates synaptic transmission and autophagy to mitigate age-related sequelae.Nature communications · 2026Article
- Elevating NeuronalbioRxiv : the preprint server for biology · 2026Article
- Proline-directed phosphorylation and prolyl isomerization oppose each other to regulate PSD-95 ubiquitination and excitatory synaptic plasticity.Frontiers in molecular neuroscience · 2026Article
- Cypin regulates K63-linked polyubiquitination to shape synaptic content.Science advances · 2025Article
- Article
- Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases.Communications biology · 2024Article
- Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Biocytin-Labeling in Whole-Cell Recording: Electrophysiological and Morphological Properties of Pyramidal Neurons in CYLD-Deficient Mice.Molecules (Basel, Switzerland) · 2023Article
- Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.Molecular psychiatry · 2023Article
- Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury.Ageing research reviews · 2023Review
- LPS-induced acute neuroinflammation, involving interleukin-1 beta signaling, leads to proteomic, cellular, and network-level changes in the prefrontal cortex of mice.Brain, behavior, & immunity - health · 2023Article
- Protective effects and mechanisms of the Erzhi formula on glucocorticoid induced primary cortical neuron injury.Frontiers in pharmacology · 2023Article
- Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum.Frontiers in molecular neuroscience · 2023Article
- Development of single-molecule ubiquitination mediated fluorescence complementation to visualize protein ubiquitination dynamics in dendrites.Cell reports · 2022Article
- Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates.Nature communications · 2022Article
- Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling.Molecular psychiatry · 2022Article
- Deubiquitinase CYLD acts as a negative regulator of dopamine neuron survival in Parkinson's disease.Science advances · 2022Article
- The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures.Molecular neurobiology · 2022Article
- The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Historical perspective and progress on protein ubiquitination at glutamatergic synapses.Neuropharmacology · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.