Mind Bomb-2 Is an E3 Ligase That Ubiquitinates the N-Methyl-D-aspartate Receptor NR2B Subunit in a Phosphorylation-dependent Manner

Gallo Research Center, Department of Neurology, University of California-San Francisco, Emeryville, CA 94608, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2008; 283(1):301-10. DOI: 10.1074/jbc.M705580200
Source: PubMed


The N-methyl-d-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity. Post-translational modifications of NMDARs, such
as phosphorylation, alter both the activity and trafficking properties of NMDARs. Ubiquitination is increasingly being recognized
as another post-translational modification that can alter synaptic protein composition and function. We identified Mind bomb-2
as an E3 ubiquitin ligase that interacts with and ubiquitinates the NR2B subunit of the NMDAR in mammalian cells. The protein-protein
interaction and the ubiquitination of the NR2B subunit were found to be enhanced in a Fyn phosphorylation-dependent manner.
Immunocytochemical studies reveal that Mind bomb-2 is localized to postsynaptic sites and colocalizes with the NMDAR in apical
dendrites of hippocampal neurons. Furthermore, we show that NMDAR activity is down-regulated by Mind bomb-2. These results
identify a specific E3 ubiquitin ligase as a novel interactant with the NR2B subunit and suggest a possible mechanism for
the regulation of NMDAR function involving both phosphorylation and ubiquitination.

    • "PSD-95 ubiquitination also results in increased AMPAR internalization, possibly through a non-proteolytic function, i.e., by interacting with and enhancing clathrin-dependent endocytosis (Bianchetta et al., 2011). Both NMDARs and AMPARs are also modified by protein ubiquitination; the NMDAR subunit GluN2B is ubiquitinated by the RING family E3 ligase Mib2 (Jurd et al., 2008), the AMPAR subunit GluA1 by Nedd4 (Lin et al., 2011), and GluA2 by an undefined E3 ligase (Lussier et al., 2011). Our results add to this list another member of postsynaptic proteins by showing that UBE3A ubiquitinates SK2 in its C-terminal domain, on lysine residues K506, K514, and K550. "
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    ABSTRACT: Gated solely by activity-induced changes in intracellular calcium, small-conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics, and Ca(2+) sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Cell Reports
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    • "Accordingly, stimulation of cerebrocortical neurons with bicuculline was shown to induce the degradation of PSD proteins by a mechanism sensitive to proteasome inhibitors (Ehlers, 2003). Key proteins in the expression of synaptic plasticity, including PSD-95 (Colledge et al., 2003), Arc (Greer et al., 2010), glutamate receptors (Nelson et al., 2006; Jurd et al., 2008), and other synaptic proteins (Hung et al., 2010), have been shown to be proteasome targets. The aurora kinase, a proteasome substrate (Huang et al., 2002), phosphorylates CPEB (cytoplasmic polyadenylation element binding protein), a protein that plays an important role in the translation of transcripts containing the cytoplasmic polyadenylation element, such as the CaMKII-. "
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    ABSTRACT: The neurotrophin brain-derived neurotrophic factor (BDNF) mediates activity-dependent long-term changes of synaptic strength in the CNS. The effects of BDNF are partly mediated by stimulation of local translation, with consequent alterations in the synaptic proteome. The ubiquitin-proteasome system (UPS) also plays an important role in protein homeostasis at the synapse by regulating synaptic activity. However, whether BDNF acts on the UPS to mediate the effects on long-term synaptic potentiation (LTP) has not been investigated. In the present study, we show similar and nonadditive effects of BDNF and proteasome inhibition on the early phase of synaptic potentiation (E-LTP) induced by theta-burst stimulation of rat hippocampal CA1 synapses. The effects of BDNF were blocked by the proteasome activator IU1, suggesting that the neurotrophin acts by decreasing proteasome activity. Accordingly, BDNF downregulated the proteasome activity in cultured hippocampal neurons and in hippocampal synaptoneurosomes. Furthermore, BDNF increased the activity of the deubiquitinating enzyme UchL1 in synaptoneurosomes and upregulated free ubiquitin. In contrast to the effects on posttetanic potentiation, proteasome activity was required for BDNF-mediated LTP. These results show a novel role for BDNF in UPS regulation at the synapse, which is likely to act together with the increased translation activity in the regulation of the synaptic proteome during E-LTP. Copyright © 2015 the authors 0270-6474/15/353319-11$15.00/0.
    Full-text · Article · Feb 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "Several different regulatory mechanisms have been identified thus far. It was recently reported that the NR2B subunit of the NMDA receptor can be ubiquitinated by the E3 ligase Mind bomb-2 (Mib2) [57]. Although it is unclear if the ubiquitination of NR2B leads to receptor endocytosis, degradation, or other downstream signaling cascades, the same study demonstrated the possibility that ubiquitination can regulate the function of the NMDA receptor. "
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    ABSTRACT: The ubiquitin proteasome system (UPS) is one of the principle mechanisms for the regulation of protein homeostasis in mammalian cells. In dynamic cellular structures such as neuronal synapses, UPS and protein translation provide an efficient way for cells to respond promptly to local stimulation and regulate neuroplasticity. The majority of research related to long-term plasticity has been focused on the postsynapses and has shown that ubiquitination and subsequent degradation of specific proteins are involved in various activity-dependent plasticity events. This review summarizes recent achievements in understanding ubiquitination of postsynaptic proteins and its impact on synapse plasticity and discusses the direction for advancing future research in the field.
    Full-text · Article · Aug 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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