Open AccessThe nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death
Author(s) -
Gabriela Zárraga-Granados,
Gabriel Muciño-Hernández,
María R. Sánchez-Carbente,
Wendy Villamizar-Gálvez,
Ana Peñas-Rincón,
Cristián Arredondo,
Marı́a Estela Andrés,
Christopher D. Wood,
Luis Covarrubias,
Susana Castro-Obregón
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0222072
Subject(s) - sumo protein , microbiology and biotechnology , autophagy , biology , programmed cell death , intracellular , subcellular localization , transcription factor , nuclear export signal , nuclear protein , cytoplasm , apoptosis , cell nucleus , ubiquitin , biochemistry , gene
NR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and post-translational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.