Neuronal SUMOylation: Mechanisms, Physiology, and Roles in Neuronal Dysfunction

Henley, Jeremy M.; Craig, Timothy; Wilkinson, Kevin A.

doi:10.1152/physrev.00008.2014

Cited by 165 publications

(240 citation statements)

References 327 publications

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“…The authors propose one possible explanation is that phosphorylation of a very small proportion of GluA1 might trigger changes in adjacent unphosphorylated AMPARs by an unknown mechanism. While further work is required, it is notable that due to their dynamic nature, other posttranslational modifications such as ubiquitination and SUMOylation affect only a very small proportion of substrate at any one time while still having a major effect on the substrate pool 137 . Notwithstanding the results of the Phos-tag study 22 , many reports have examined how phosphorylation differentially traffics CP-versus CI-AMPARs and accumulating evidence points to PKA-mediated phosphorylation of S845 in GluA1 as an important determinant in GluA1-containing CP-AMPAR trafficking in hippocampal LTP, LTD and homeostatic scaling (Fig.…”

Section: Ampar Phosphorylationmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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Section: Ampar Phosphorylationmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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“…[1][2][3] It is now known that SUMO proteins are transferred via covalent interaction through the E1-SUMO-activating, E2-SUMO-conjugating, and E3-SUMO-ligating enzyme cascade allowing for recognition and binding to SUMO-targeted lysine residues. 4 Despite evidence that SUMOylation is a transient and reversible modification typically bound to only »1% of SUMO-targeted lysine residues, 5 the consequences of protein SUMOylation are numerous. The rapid turnover of SUMOylation has led to the hypothesis that the effects of protein SUMOylation persist long after the modification has been lost.…”

Section: Introductionmentioning

confidence: 99%

“…Put another way, only »1% of substrate might be SUMOylated but a much greater fraction of protein may have undergone recent SUMOylation and this may be sufficient to actively exert longer-term effects of the modification on the protein's function. 6 The effects of protein SUMOylation include alteration of conformation, regulation of stability via competition with ubiquitin modifications, and alteration of interactome via enhancement or restriction of interaction with protein binding partners (see 4 for review). Predicting clients for protein SUMOylation originally relied on protein sequence comparison to the canonical SUMOylation consensus sequence.…”

Section: Introductionmentioning

confidence: 99%

A single structurally conserved SUMOylation site in CRMP2 controls NaV1.7 function

et al. 2017

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The neuronal collapsin response mediator protein 2 (CRMP2) undergoes several posttranslational modifications that codify its functions. Most recently, CRMP2 SUMOylation (addition of small ubiquitin like modifier (SUMO)) was identified as a key regulatory step within a modification program that codes for CRMP2 interaction with, and trafficking of, voltage-gated sodium channel NaV1.7. In this paper, we illustrate the utility of combining sequence alignment within protein families with structural analysis to identify, from several putative SUMOylation sites, those that are most likely to be biologically relevant. Co-opting this principle to CRMP2, we demonstrate that, of 3 sites predicted to be SUMOylated in CRMP2, only the lysine 374 site is a SUMOylation client. A reduction in NaV1.7 currents was the corollary of the loss of CRMP2 SUMOylation at this site. A 1.78-A -resolution crystal structure of mouse CRMP2 was solved using X-ray crystallography, revealing lysine 374 as buried within the CRMP2 tetramer interface but exposed in the monomer. Since CRMP2 SUMOylation is dependent on phosphorylation, we postulate that this state forces CRMP2 toward a monomer, exposing the SUMO site and consequently, resulting in constitutive regulation of NaV1.7.

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“…38,39 In this regard, our data show that FKBP51 SUMOylation is increased under heat-shock stress in a hippocampal neuronal context and raises thus the interesting possibility that SUMO conjugation to FKBP51 during Figure 6 SUMO conjugation to FKBP51 regulates GR signaling. Modification of FKBP51 by SUMO attachment promotes its interaction with Hsp90 and its recruitment to the GR chaperone complex.…”

Section: Discussionmentioning

confidence: 72%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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Neuronal SUMOylation: Mechanisms, Physiology, and Roles in Neuronal Dysfunction

Cited by 165 publications

References 327 publications

Synaptic AMPA receptor composition in development, plasticity and disease

Synaptic AMPA receptor composition in development, plasticity and disease

A single structurally conserved SUMOylation site in CRMP2 controls NaV1.7 function

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

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