PT - JOURNAL ARTICLE AU - Meenakshi Basu Shrivastava AU - Barbara Mojsa AU - Stéphan Mora AU - Ian Robbins AU - Guillaume Bossis AU - Iréna Lassot AU - Solange Desagher TI - Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3 AID - 10.1101/2020.09.29.317958 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.09.29.317958 4099 - http://biorxiv.org/content/early/2020/09/29/2020.09.29.317958.short 4100 - http://biorxiv.org/content/early/2020/09/29/2020.09.29.317958.full AB - NFATc3 is the predominant member of the NFAT family of transcription factor in neurons, where it plays a pro-apoptotic role. Mechanisms controlling NFAT protein stability are poorly understood. Here we identify Trim39 as an E3 ubiquitin-ligase of NFATc3. Indeed, Trim39 ubiquitinates NFATc3 in vitro and in cells, whereas silencing of endogenous Trim39 decreases NFATc3 ubiquitination. We also show that Trim17 inhibits Trim39-mediated ubiquitination of NFATc3 by reducing both the E3 ubiquitin-ligase activity of Trim39 and the NFATc3/Trim39 interaction. Moreover, mutation of SUMOylation sites in NFATc3 or SUMO-interacting motif in Trim39 reduces the NFATc3/Trim39 interaction and Trim39-induced ubiquitination of NFATc3. As a consequence, silencing of Trim39 increases the protein level and transcriptional activity of NFATc3, resulting in enhanced neuronal apoptosis. Likewise, a SUMOylation-deficient mutant of NFATc3 exhibits increased stability and pro-apoptotic activity. Taken together, these data indicate that Trim39 modulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for NFATc3.Competing Interest StatementThe authors have declared no competing interest.