Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3

Meenakshi Basu-Shrivastava (1) , Barbara Mojsa (1) , Stéphan Mora (1) , Ian Robbins (1) , Guillaume Bossis (1) , Irena Lassot (1) , Solange Desagher (1)

1 IGMM - Institut de Génétique Moléculaire de Montpellier

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.

Domaines: Organisation et fonctions cellulaires [q-bio.SC]; Biochimie [q-bio.BM]; Biologie moléculaire

Meenakshi Basu-Shrivastava, Barbara Mojsa, Stéphan Mora, Ian Robbins, Guillaume Bossis, et al.. Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3. Cell Death and Differentiation, 2022, ⟨10.1038/s41418-022-01002-2⟩. ⟨hal-03033907v2⟩