Receptor Trafficking and the Regulation of Synaptic Plasticity by SUMO

Luo, Jia; Ashikaga, Emi; Rubin, Philip; Heimann, Michaela J.; Hildick, Keri L; Bishop, Paul; Girach, Fatima; Josa-Prado, Fernando; Tang, Leo T.H.; Carmichael, Ruth E.; Henley, Jeremy M.; Wilkinson, Kevin A.

doi:10.1007/s12017-013-8253-y

Cited by 32 publications

(30 citation statements)

References 117 publications

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“…It was argued previously that the His 6 -HA tag added to SUMO1 in the His 6 -HA-SUMO1 KI might prevent SUMO1 from modifying key substrates or that the reduction of global SUMO1 levels in His 6 -HA-SUMO1 KI that we previously reported and described above (Figure 1—figure supplement 1) may account for the absence of SUMO1 signal at synapses in His 6 -HA-SUMO1 KI neurons as compared to WT samples (Tirard et al, 2012; Henley et al, 2014; Luo et al, 2013). Therefore, we decided to evaluate how anti-SUMO1 immunolabelling differed from the anti-HA labelling observed in the His 6 -HA-SUMO1 KI (Figures 7, 8 and 9), especially in the synaptic compartment.…”

Section: Resultsmentioning

confidence: 63%

“…Previous reports indicated the presence of multiple SUMO1-conjugates in synaptosome fractions prepared from mouse or rat brain (Martin et al, 2007; Luo et al, 2013), leading to the proposal that SUMO1-conjugated proteins are present at synapses. To test this notion, we sub-fractionated cortices of His 6 -HA-SUMO1 KI and SUMO1 KO mice by standard sub-fractionation protocols.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of SUMO1-conjugation at synapses

Daniel

Cooper

Palvimo

et al. 2017

eLife

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SUMO1-conjugation of proteins at neuronal synapses is considered to be a major post-translational regulatory process in nerve cell and synapse function, but the published evidence for SUMO1-conjugation at synapses is contradictory. We employed multiple genetic mouse models for stringently controlled biochemical and immunostaining analyses of synaptic SUMO1-conjugation. By using a knock-in reporter mouse line expressing tagged SUMO1, we could not detect SUMO1-conjugation of seven previously proposed synaptic SUMO1-targets in the brain. Further, immunostaining of cultured neurons from wild-type and SUMO1 knock-out mice showed that anti-SUMO1 immunolabelling at synapses is non-specific. Our findings indicate that SUMO1-conjugation of synaptic proteins does not occur or is extremely rare and hence not detectable using current methodology. Based on our data, we discuss a set of experimental strategies and minimal consensus criteria for the validation of SUMOylation that can be applied to any SUMOylation substrate and SUMO isoform.DOI: http://dx.doi.org/10.7554/eLife.26338.001

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Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Analysis of SUMO1-conjugation at synapses

Daniel

Cooper

Palvimo

et al. 2017

eLife

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“…Biochemical and imaging experiments have defined SUMO as one of many regulators of synaptic plasticity, contributing, for example, to the regulation of receptors trafficking during the induction of chemical LTP (Luo et al, 2013). Indeed, induction of chemical LTP in cultured neurons with glycine induces the expression of SUMO-1 and Ubc9 (Jaafari et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3

Drisaldi¹,

Colnaghi²,

Fioriti³

et al. 2015

Cell Reports

111

140

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Summary Protein synthesis is crucial for the maintenance of long-term-memory-related synaptic plasticity. The prion-like cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates the translation of several mRNAs important for long-term synaptic plasticity in the hippocampus. Here, we provide evidence that the prion-like aggregation and activity of CPEB3 is controlled by SUMOylation. In the basal state, CPEB3 is a repressor and is soluble. Under these circumstances, CPEB3 is SUMOylated in hippocampal neurons both in vitro and in vivo. Following neuronal stimulation, CPEB3 is converted into an active form that promotes the translation of target mRNAs, and this is associated with a decrease of SUMOylation and an increase of aggregation. A chimeric CPEB3 protein fused to SUMO cannot form aggregates and cannot activate the translation of target mRNAs. These findings suggest a model whereby SUMO regulates translation of mRNAs and structural synaptic plasticity by modulating the aggregation of the prion-like protein CPEB3.

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“…SUMOylation is dependent on the presence of Ubc9 (Bhaskar et al 2000), and Ubc9 mutants display impaired SUMOylation of substrates (Miles et al 2008). The genetic interaction between HDAC4 and Ubc9 was particularly interesting as a growing body of evidence indicates that SUMOylation is an important mechanism for regulation of neuronal protein activity (Henley et al 2014) and for regulation of memory formation (Yang et al 2012;Castro-Gomez et al 2013;Luo et al 2013;Chen et al 2014;Wang et al 2014;Drisaldi et al 2015). Moreover, HDAC4 has also been implicated as a putative E3 SUMO ligase, as its presence enhances the SUMOylation of MEF2 (Gregoire and Yang 2005;Zhao et al 2005) and of the androgen receptor (Yang et al 2011) in mammalian cells.…”

Section: Hdac4 Interacts With the Sumoylation Machinerymentioning

confidence: 99%

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

et al. 2016

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HDAC4 is a potent memory repressor with overexpression of wild type or a nuclear-restricted mutant resulting in memory deficits. Interestingly, reduction of HDAC4 also impairs memory via an as yet unknown mechanism. Although histone deacetylase family members are important mediators of epigenetic mechanisms in neurons, HDAC4 is predominantly cytoplasmic in the brain and there is increasing evidence for interactions with nonhistone proteins, suggesting HDAC4 has roles beyond transcriptional regulation.To that end, we performed a genetic interaction screen in Drosophila and identified 26 genes that interacted with HDAC4, including Ubc9, the sole SUMO E2-conjugating enzyme. RNA interference-induced reduction of Ubc9 in the adult brain impaired long-term memory in the courtship suppression assay, a Drosophila model of associative memory. We also demonstrate that HDAC4 and Ubc9 interact genetically during memory formation, opening new avenues for investigating the mechanisms through which HDAC4 regulates memory formation and other neurological processes.KEYWORDS histone deacetylase; SUMOylation; plasticity; neuron; memory T HE histone deacetylase HDAC4 is widely expressed in neurons throughout the brain (Darcy et al. 2010) and an increasing body of evidence indicates that HDAC4 plays important roles in neurological function Chen and Cepko 2009;Kim et al. 2012;Li et al. 2012;Sando et al. 2012;Sarkar et al. 2014). To that end, we recently demonstrated that in Drosophila, RNA interference (RNAi)-mediated knockdown of HDAC4 in the adult brain impairs long-term memory (LTM) in the courtship suppression assay, a model of associative memory (Fitzsimons et al. 2013). Similarly in humans, loss of one copy of HDAC4 correlates with brachydactyly mental retardation syndrome (BDMR), the neurological symptoms of which include intellectual disability and autism (Williams et al. 2010;Morris et al. 2012;Villavicencio-Lorini et al. 2013), and in mice, conditional knockout of HDAC4 in the brain results in impairments in hippocampal-dependent associative LTM . Despite this growing evidence of a critical role, the mechanism(s) through which HDAC4 positively influences LTM is unknown. This is in part because HDAC4 exists in both nuclear and cytoplasmic pools, and under basal conditions, the majority of HDAC4 is localized to the cytoplasm (Chawla et al. 2003;Darcy et al. 2010). Given the predominant nonnuclear localization, particularly the concentration of HDAC4 at dendritic spines (Darcy et al. 2010), we hypothesize that cytoplasmic HDAC4 is required in memory formation; however, the mechanisms through which HDAC4 acts outside the nucleus are unknown.The nuclear role of HDAC4 is less of an enigma. When in the nucleus, HDAC4 acts as a transcriptional repressor; although vertebrate HDAC4 is catalytically inactive as a histone deacetylase, rather it facilitates changes in gene expression through direct binding and inhibition of transcription factors such as MEF2 (Miska et al. 1999;Wang et al. 1999;Lu et al. 2000). As described abov...

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Receptor Trafficking and the Regulation of Synaptic Plasticity by SUMO

Cited by 32 publications

References 117 publications

Analysis of SUMO1-conjugation at synapses

Analysis of SUMO1-conjugation at synapses

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

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