Ubiquitination of  -synuclein by Siah-1 promotes  -synuclein aggregation and apoptotic cell death

Lee, James T.; Wheeler, Tiffany C.; Li, Lian; Chin, Lih‐Shen

doi:10.1093/hmg/ddm363

Cited by 162 publications

(154 citation statements)

References 75 publications

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“…Similarly, it has also been shown that CaM binding to mGluR5 inhibits the binding of the E3 ligase Siah-1A in vitro (13). Recently Siah-1A has been shown to promote monoubiquitination of ␣-synuclein, leading to its aggregation (35). It is possible that the effects of CaM on mGluR5 trafficking observed in our study are a consequence of changes in Siah-1A-dependent ubiquitination of mGluR5; however, direct evidence for this hypothesis awaits further experimentation.…”

Section: Discussionsupporting

confidence: 62%

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Lee

Choi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Metabotropic glutamate receptors (mGluRs) 1-8 are G proteincoupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca 2؉ signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca 2؉ oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.phosphorylation ͉ protein kinase C ͉ receptor trafficking T he group I metabotropic glutamate receptor mGluR5 is highly expressed in the forebrain, where it regulates synaptic plasticity (1, 2). In addition, mGluR5 plays a role in pain (3) and addiction (4) and in neurological disorders such as fragile X syndrome (5, 6). Group I mGluRs are G protein-coupled receptors (GPCRs), which are coupled to phospholipase C, and receptor activation triggers phosphoinositide turnover, release of intracellular Ca 2ϩ , and activation of Protein Kinase C (PKC) (7). Although PKC activity regulates mGluR5-mediated Ca 2ϩ signaling and receptor function (8-11), there are no studies linking PKC phosphorylation of mGluR5 to receptor surface expression, endocytosis, or intracellular trafficking.Like other GPCRs, mGluR5 interacts with many proteins in addition to the guanine nucleotide-binding proteins (G proteins). Most of the binding sites for these protein-protein interactions reside within the long intracellular C-terminal domain of mGluR5, suggesting that this region is critical in the functional regulation of mGluR5. For example, the Homer proteins bind to the PPxxFR motif within the distal C terminus, the Tamalin protein associates with the distal C terminus, and calmodulin (CaM) and the E3 ligase Siah-1A bind to the first one-third of the mGluR5 C terminus (12-15). However, the dynamic regulation of these protein-protein interactions has not been described. CaM is a particularly intriguing candidate as an mGluR5 regulator because of its Ca 2ϩ dependence and its key role in synaptic plasticity (16,17). Furthermore, CaM binding to other GPCRs, including dopamine, opioid, and serotonin receptors, has been documented, consistent with a conserved regulatory role for CaM in regulating . We now show that PKC phosphorylation of serine 901 (S901) on mGluR5 inhibits CaM binding and decreases mGluR5 surface expression. Furthermore, preve...

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Section: Discussionsupporting

confidence: 62%

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Lee

Choi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…16,17 Mass spectrometry analysis reveals that SIAH monoubiquitinates α-synuclein at several lysines, including 12, 21 and 23, 16 which were previously found to be monoubiquitinated in purified Lewy bodies. 8 A reason for skepticism regarding a possible role of α-synuclein ubiquitination in Lewy body formation comes from the observation that only a small fraction (about 10%) of α-synuclein is ubiquitinated in Lewy bodies.…”

Section: Role Of Ubiquitin In α-Synuclein Aggregationmentioning

confidence: 91%

“…18 On the other hand, Liu et al recently found that the α-synuclein A30P mutant was not efficiently ubiquitinated by SIAH. 17 The reason for this apparent discrepancy is not clear.…”

Section: Role Of Ubiquitin In α-Synuclein Aggregationmentioning

confidence: 99%

Ubiquitination of α-synuclein and autophagy in Parkinson's disease

Engelender¹

2008

Autophagy

104

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“…Although some ubiquitin-ligases can polyubiquitinate α-synuclein (6-8), the E3 ubiquitin-ligase responsible for α-synuclein monoubiquitination has remained obscure. We and others have recently shown that α-synuclein is monoubiquitinated by the E3 ubiquitin-ligase SIAH both in vitro and in vivo (9)(10)(11). SIAH is present in Lewy bodies (9) and monoubiquitinates α-synuclein at the same lysine residues that are monoubiquitinated in α-synuclein immunopurified from Lewy bodies (5,10).…”

mentioning

confidence: 91%

α-Synuclein fate is determined by USP9X-regulated monoubiquitination

Rott

Szargel

Haskin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

160

145

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α-Synuclein is central to the pathogenesis of Parkinson disease (PD). Mutations as well as accumulation of α-synuclein promote the death of dopaminergic neurons and the formation of Lewy bodies. α-Synuclein is monoubiquitinated by SIAH, but the regulation and roles of monoubiquitination in α-synuclein biology are poorly understood. We now report that the deubiquitinase USP9X interacts in vivo with and deubiquitinates α-synuclein. USP9X levels are significantly lower in cytosolic fractions of PD substantia nigra and Diffuse Lewy Body disease (DLBD) cortices compared to controls. This was associated to lower deubiquitinase activity toward monoubiquitinated α-synuclein in DLBD cortical extracts. A fraction of USP9X seems to be aggregated in PD and DLBD, as USP9X immunoreactivity is detected in Lewy bodies. Knockdown of USP9X expression promotes accumulation of monoubiquitinated α-synuclein species and enhances the formation of toxic α-synuclein inclusions upon proteolytic inhibition. On the other hand, by manipulating USP9X expression levels in the absence of proteolytic impairment, we demonstrate that monoubiquitination controls the partition of α-synuclein between different protein degradation systems. Deubiquitinated α-synuclein is mostly degraded by autophagy, while monoubiquitinated α-synuclein is preferentially degraded by the proteasome. Moreover, monoubiquitination promotes the degradation of α-synuclein, whereas deubiquitination leads to its accumulation, suggesting that the degradation of deubiquitinated α-synuclein by the autophagy pathway is less efficient than the proteasomal one. Lower levels of cytosolic USP9X and deubiquitinase activity in α-synucleinopathies may contribute to the accumulation and aggregation of monoubiquitinated α-synuclein in Lewy bodies. Our data indicate that monoubiquitination is a key determinant of α-synuclein fate. P arkinson disease (PD) is mainly characterized by the death of dopaminergic neurons in the substantia nigra and presence of inclusions called Lewy bodies. Even though Lewy bodies are composed predominantly of α-synuclein, the mechanisms by which Lewy bodies are formed and their role in the death of dopaminergic neurons remain elusive (1, 2).α-Synuclein purified from Lewy bodies is monoubiquitinated (3-5). Although some ubiquitin-ligases can polyubiquitinate α-synuclein (6-8), the E3 ubiquitin-ligase responsible for α-synuclein monoubiquitination has remained obscure. We and others have recently shown that α-synuclein is monoubiquitinated by the E3 ubiquitin-ligase SIAH both in vitro and in vivo (9-11). SIAH is present in Lewy bodies (9) and monoubiquitinates α-synuclein at the same lysine residues that are monoubiquitinated in α-synuclein immunopurified from Lewy bodies (5, 10). Most importantly, we found that in the presence of proteolytic inhibitors, monoubiquitination of α-synuclein promoted by SIAH leads to a marked increase in the aggregation of α-synuclein and formation of inclusions, which are toxic to cells (10-12). Therefore, our data indicate that monou...

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Ubiquitination of -synuclein by Siah-1 promotes -synuclein aggregation and apoptotic cell death

Cited by 162 publications

References 75 publications

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Ubiquitination of α-synuclein and autophagy in Parkinson's disease

α-Synuclein fate is determined by USP9X-regulated monoubiquitination

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