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

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...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2017-10, Vol.114 (41), p.E8760-E8769
Hauptverfasser: Ma, Qi, Ruan, Hongyu, Peng, Lisheng, Zhang, Mingjie, Gack, Michaela U., Yao, Wei-Dong
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container_issue 41
container_start_page E8760
container_title Proceedings of the National Academy of Sciences - PNAS
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creator Ma, Qi
Ruan, Hongyu
Peng, Lisheng
Zhang, Mingjie
Gack, Michaela U.
Yao, Wei-Dong
description 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.
doi_str_mv 10.1073/pnas.1620153114
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subjects Biological Sciences
Brain
Chains
Degradation
Density
Glutamic acid receptors (ionotropic)
Hippocampus
Long-term depression
Lysine
Machinery and equipment
Mental depression
N-Methyl-D-aspartic acid receptors
Plastic properties
Plasticity
PNAS Plus
Postsynaptic density
Postsynaptic density proteins
Proteases
Proteasomes
Proteins
Receptors
Scaffolding
Substrates
Synapses
Synaptic depression
Synaptic plasticity
Synaptic strength
Synaptogenesis
TRAF6 protein
Tumor necrosis factor
Tumor necrosis factor receptors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
title Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity
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