title: Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17.
abstract: Neuronal apoptosis induced by survival factor deprivation is strongly regulated at the transcriptional level. Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the control of the survival/death fate of neurons. However, the mechanisms that regulate NFAT activity in response to apoptotic stimuli and the target genes that mediate their effect on neuronal apoptosis are mostly unknown. In a previous study, we identified Trim17 as a crucial E3 ubiquitin ligase that is necessary and sufficient for neuronal apoptosis. Here, we show that Trim17 binds preferentially SUMOylated forms of NFATc3. Nonetheless, Trim17 does not promote the ubiquitination/degradation of NFATc3. NFAT transcription factors are regulated by calcium/calcineurin-dependent nuclear-cytoplasmic shuttling. Interestingly, Trim17 reduced by twofold the calcium-mediated nuclear localization of NFATc3 and, consistent with this, halved NFATc3 activity, as estimated by luciferase assays and by measurement of target gene expression. Trim17 also inhibited NFATc4 nuclear translocation and activity. NFATc4 is known to induce the expression of survival factors and, as expected, overexpression of NFATc4 protected cerebellar granule neurons from serum/KCl deprivation-induced apoptosis. Inhibition of NFATc4 by Trim17 may thus partially mediate the proapoptotic effect of Trim17. In contrast, overexpression of NFATc3 aggravated neuronal death, whereas knockdown of NFATc3 protected neurons from apoptosis. This proapoptotic effect of NFATc3 might be due to a feedback loop in which NFATc3, but not NFATc4, induces the transcription of the proapoptotic gene Trim17. Indeed, we found that overexpression or silencing of NFATc3, respectively, increased or decreased Trim17 levels, whereas NFATc4 had no significant effect on Trim17 expression. Moreover, we showed that NFATc3 binds to the promoter of the Trim17 gene together with c-Jun. Therefore, our results describe a novel mechanism regulating NFAT transcription factors beyond the calcium/calcineurin-dependent pathway and provide a possible explanation for the opposite effects of NFATc3 and NFATc4 on neuronal apoptosis.
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, Montpellier 34293, France [2] Université Montpellier 2, Montpellier 34095, France [3] Université Montpellier 1, Montpellier 34967, France.
authors.forename: B
authors.initials: B
authors.lastname: Mojsa
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, Montpellier 34293, France [2] Université Montpellier 2, Montpellier 34095, France [3] Université Montpellier 1, Montpellier 34967, France.
authors.forename: S
authors.initials: S
authors.lastname: Mora
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, Montpellier 34293, France [2] Université Montpellier 2, Montpellier 34095, France [3] Université Montpellier 1, Montpellier 34967, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Bossowski
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, Montpellier 34293, France [2] Université Montpellier 2, Montpellier 34095, France [3] Université Montpellier 1, Montpellier 34967, France.
authors.forename: I
authors.initials: I
authors.lastname: Lassot
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, Montpellier 34293, France [2] Université Montpellier 2, Montpellier 34095, France [3] Université Montpellier 1, Montpellier 34967, France.
authors.forename: S
authors.initials: S
authors.lastname: Desagher
mesh_terms: D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D016758:Genes, jun; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; C494009:Nfatc3 protein, mouse; D034741:RNA, Small Interfering; D000070584:Tripartite Motif Proteins; C115437:TRIM17 protein, human; C485451:Trim17 protein, mouse; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D002118:Calcium