RGD Reference Report - Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity. - Rat Genome Database

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Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity.

Authors: Ma, Qi  Ruan, Hongyu  Peng, Lisheng  Zhang, Mingjie  Gack, Michaela U  Yao, Wei-Dong 
Citation: Ma Q, etal., Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8760-E8769. doi: 10.1073/pnas.1620153114. Epub 2017 Sep 25.
RGD ID: 405650304
Pubmed: PMID:28973854   (View Abstract at PubMed)
PMCID: PMC5642675   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1620153114   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CyldRatregulation of neurotransmitter receptor localization to postsynaptic specialization membrane involved_inIDA PMID:28973854SynGO 
CyldRatregulation of neurotransmitter receptor localization to postsynaptic specialization membrane involved_inIMP PMID:28973854SynGO 
CyldRatregulation protein catabolic process at postsynapse involved_inIMP PMID:28973854SynGO 
CyldRatregulation protein catabolic process at postsynapse involved_inIEP PMID:28973854SynGO 
CyldRatregulation protein catabolic process at postsynapse involved_inIDA PMID:28973854SynGO 
Traf6Ratregulation protein catabolic process at postsynapse involved_inIMP PMID:28973854SynGO 
Traf6Ratregulation protein catabolic process at postsynapse involved_inIEP PMID:28973854SynGO 
Traf6Ratregulation protein catabolic process at postsynapse involved_inIDA PMID:28973854SynGO 
Ube2nRatregulation protein catabolic process at postsynapse involved_inIDA PMID:28973854SynGO 
Ube2nRatregulation protein catabolic process at postsynapse involved_inIEP PMID:28973854SynGO 
Ube2nRatregulation protein catabolic process at postsynapse involved_inIMP PMID:28973854SynGO 
Ube2v1Ratregulation protein catabolic process at postsynapse involved_inIDA PMID:28973854SynGO 
Ube2v1Ratregulation protein catabolic process at postsynapse involved_inIEP PMID:28973854SynGO 
Ube2v1Ratregulation protein catabolic process at postsynapse involved_inIMP PMID:28973854SynGO 
Ube2v1-ps22Ratregulation protein catabolic process at postsynapse involved_inIDA PMID:28973854SynGO 
Ube2v1-ps22Ratregulation protein catabolic process at postsynapse involved_inIEP PMID:28973854SynGO 
Ube2v1-ps22Ratregulation protein catabolic process at postsynapse involved_inIMP PMID:28973854SynGO 
Ube2v1l1Ratregulation protein catabolic process at postsynapse involved_inIDA PMID:28973854SynGO 
Ube2v1l1Ratregulation protein catabolic process at postsynapse involved_inIEP PMID:28973854SynGO 
Ube2v1l1Ratregulation protein catabolic process at postsynapse involved_inIMP PMID:28973854SynGO 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CyldRatglutamatergic synapse is_active_inIMP PMID:28973854SynGO 
CyldRatglutamatergic synapse is_active_inIEP PMID:28973854SynGO 
CyldRatglutamatergic synapse is_active_inIDA PMID:28973854SynGO 
Traf6Ratglutamatergic synapse is_active_inIMP PMID:28973854SynGO 
Traf6Ratglutamatergic synapse is_active_inIEP PMID:28973854SynGO 
Traf6Ratglutamatergic synapse is_active_inIDA PMID:28973854SynGO 
Ube2nRatglutamatergic synapse is_active_inIDA PMID:28973854SynGO 
Ube2nRatglutamatergic synapse is_active_inIEP PMID:28973854SynGO 
Ube2nRatglutamatergic synapse is_active_inIMP PMID:28973854SynGO 
Ube2v1Ratglutamatergic synapse is_active_inIDA PMID:28973854SynGO 
Ube2v1Ratglutamatergic synapse is_active_inIEP PMID:28973854SynGO 
Ube2v1Ratglutamatergic synapse is_active_inIMP PMID:28973854SynGO 
Ube2v1-ps22Ratglutamatergic synapse is_active_inIDA PMID:28973854SynGO 
Ube2v1-ps22Ratglutamatergic synapse is_active_inIEP PMID:28973854SynGO 
Ube2v1-ps22Ratglutamatergic synapse is_active_inIMP PMID:28973854SynGO 
Ube2v1l1Ratglutamatergic synapse is_active_inIDA PMID:28973854SynGO 
Ube2v1l1Ratglutamatergic synapse is_active_inIEP PMID:28973854SynGO 
Ube2v1l1Ratglutamatergic synapse is_active_inIMP PMID:28973854SynGO 
Traf6Ratpostsynapse is_active_inIDA PMID:28973854SynGO 
Traf6Ratpostsynapse is_active_inIEP PMID:28973854SynGO 
Ube2nRatpostsynapse is_active_inIDA PMID:28973854SynGO 
Ube2nRatpostsynapse is_active_inIEP PMID:28973854SynGO 
Ube2v1Ratpostsynaptic density is_active_inIDA PMID:28973854SynGO 
Ube2v1Ratpostsynaptic density is_active_inIEP PMID:28973854SynGO 
Ube2v1-ps22Ratpostsynaptic density is_active_inIDA PMID:28973854SynGO 
Ube2v1-ps22Ratpostsynaptic density is_active_inIEP PMID:28973854SynGO 
Ube2v1l1Ratpostsynaptic density is_active_inIDA PMID:28973854SynGO 
Ube2v1l1Ratpostsynaptic density is_active_inIEP PMID:28973854SynGO 

Objects Annotated

Genes (Rattus norvegicus)
Cyld  (CYLD lysine 63 deubiquitinase)
Traf6  (TNF receptor associated factor 6)
Ube2n  (ubiquitin-conjugating enzyme E2N)
Ube2v1  (ubiquitin conjugating enzyme E2 V1)
Ube2v1-ps22  (ubiquitin conjugating enzyme E2 V1, pseudogene 22)
Ube2v1l1  (ubiquitin conjugating enzyme E2 V1 like 1)


Additional Information