Trim17, a novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Lassot, Irina; Robbins, Ian; Kristiansen, Mark; Rahmeh, Rita; Jaudon, Fanny; Magiera, Maria M.; Mora, Stéphan; Vanhille, Laurent; Липкин, А.В.; Pettmann, Brigitte; Ham, Jonathan; Desagher, Solange

doi:10.1038/cdd.2010.73

Cited by 45 publications

(85 citation statements)

References 42 publications

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“…33,34 We and others have demonstrated that Trim17 is a bona fide E3 ubiquitin-ligase. 25,35 In addition, we have shown that the E3 activity of Trim17 is both necessary and sufficient for the initiation of neuronal apoptosis. 25 Recently, human TRIM17 has been found to stimulate the proteasome-dependent degradation of the kinetochore protein ZWINT.…”

Section: Discussionmentioning

confidence: 90%

“…25,35 In addition, we have shown that the E3 activity of Trim17 is both necessary and sufficient for the initiation of neuronal apoptosis. 25 Recently, human TRIM17 has been found to stimulate the proteasome-dependent degradation of the kinetochore protein ZWINT. 36 Nevertheless, whether ZWINT is a genuine substrate of TRIM17 has not been demonstrated.…”

Section: Discussionmentioning

confidence: 90%

“…This is of crucial importance, as targeting the specific interaction between Mcl-1 and the enzymes regulating its Trim17, a Mcl-1 E3 ubiquitin-ligase in neurons MM Magiera et al stability might be used to improve neuronal survival in pathological conditions. High levels of Trim17 mRNA have been detected not only in apoptotic neurons 25 but also in organs with a high rate of apoptosis such as testis, spleen and thymus. 35 Future work will determine whether Trim17 can mediate the degradation of Mcl-1 and control the initiation of apoptosis in non-neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Primary cultures of CGNs were prepared from 7-day-old murine pups (C57Bl/6 J mice) as described previously. 25 Briefly, freshly dissected cerebella were dissociated by trypsinization and mechanical disruption, and plated in Basal Medium Eagle (BME) medium supplemented with 10% fetal bovine serum, 2 mM L-Gln, 10 mM HEPES, penicillin-streptomycin 100 IU/ml-100 mg/ml and 20 mM KCl.…”

Section: Methodsmentioning

confidence: 99%

“…Neuronal viability was assessed in triplicate by MTT assay as described previously. 25 For immunofluorescence analysis, CGNs were seeded onto glass coverslips coated with poly-D-lysine and laminin. After induction of apoptosis in the presence or absence of inhibitors, neurons were fixed with paraformaldehyde and detection of nuclear condensation, caspase 3 activation and cytochrome c release was performed as described previously.…”

Section: Methodsmentioning

confidence: 99%

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Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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Short-term proteasome inhibition has been shown to prevent neuronal apoptosis. However, the key pro-survival proteins that must be degraded for triggering neuronal death are mostly unknown. Here, we show that Mcl-1, an anti-apoptotic Bcl-2 family member, is degraded by the proteasome during neuronal apoptosis. Using primary cultures of cerebellar granule neurons deprived of serum and KCl, we found that ubiquitination and proteasomal degradation of Mcl-1 depended on its prior phosphorylation by GSK3, providing the first insight into post-translational regulation of Mcl-1 in neurons. In a previous study, we have reported that the E3 ubiquitin-ligase Trim17 is both necessary and sufficient for neuronal apoptosis. Here, we identified In the nervous system, apoptosis plays a critical role both during development and in neurodegenerative diseases. 1 In many neuronal types, apoptosis is triggered through the intrinsic pathway of caspase activation that involves the release of cytochrome c from mitochondria. The proteins of the Bcl-2 family, that comprises both anti-apoptotic (Bcl-2, Bcl-x L , Mcl-1y) and pro-apoptotic members (Bax, Bak, Bimy), play an essential role in the regulation of apoptosis by controlling the integrity of the outer mitochondrial membrane and the release of apoptogenic factors such as cytochrome c. 2 Amongst the anti-apoptotic proteins of the Bcl-2 family, Mcl-1 (Myeloid cell leukemia 1) is characterized by a short half-life. 3 Its rapid degradation by the proteasome has been shown to be required for initiation of the apoptotic cascade in several cell lines. [4][5][6][7] For a long time, little attention was paid to a potential role for Mcl-1 in the nervous system because initial studies did not detect it in neurons. However, Mcl-1 is expressed in cerebellar granule neurons (CGNs) in vivo, 8 and Mcl-1 expression has been associated with neuroprotection in the hippocampus. 9 More recently, elegant studies using different conditional Mcl-1 mouse mutants, showed that Mcl-1 is required for neuronal development, that loss of Mcl-1 sensitizes neurons to DNA damage-induced apoptosis and that Mcl-1 negatively regulates autophagy in starved neurons. 10,11 Therefore, Mcl-1 appears to play a crucial role in neuronal survival. Nevertheless, post-translational regulation of Mcl-1 has never been studied in neurons.In the present study, we report for the first time that Mcl-1 is degraded by the proteasome during neuronal apoptosis. We found that Mcl-1 degradation depended on its prior phosphorylation by glycogen synthase kinase 3 (GSK3), in primary cultures of CGNs deprived of serum and KCl. This phosphorylation of Mcl-1 favored its physical interaction with Trim17, a novel E3 ubiquitin-ligase involved in neuronal apoptosis. Moreover, our present data provide evidence that Trim17 contributes to the ubiquitination and the proteasomal degradation of Mcl-1 in neurons. As such, we define a novel molecular mechanism for regulation of Mcl-1 and initiation of apoptosis. ResultsMcl-1 is degraded by the proteasome during...

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Jabbari

Woodside

Tan

et al. 2018

Annals of Neurology

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ObjectiveThe basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome‐wide association study (GWAS) to identify genetic determinants of PSP phenotype.MethodsTwo independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non‐RS groups. We carried out separate logistic regression GWASs to compare RS and non‐RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non‐RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene‐based association testing.ResultsOur lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome‐wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2–10.0, p = 1.7 × 10−9). rs564309 is an intronic variant of the tripartite motif‐containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene‐based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.InterpretationOur study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease‐modifying therapies. Ann Neurol 2018;84:485–496

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Tripartite Motif Protein Family in Central Nervous System Diseases

Pan

et al. 2023

Cell Mol Neurobiol

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Trim17, a novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Cited by 45 publications

References 42 publications

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Tripartite Motif Protein Family in Central Nervous System Diseases

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