The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

PLoS One. 2020 Mar 25;15(3):e0222072. doi: 10.1371/journal.pone.0222072. eCollection 2020.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagic Cell Death / genetics*
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • HEK293 Cells
  • Humans
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Phosphorylation / genetics
  • Protein Stability
  • Receptors, Neurokinin-1 / genetics
  • Receptors, Neurokinin-1 / metabolism
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Substance P / metabolism
  • Sumoylation / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation / genetics
  • Transfection

Substances

  • NR4A1 protein, human
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Receptors, Neurokinin-1
  • Small Ubiquitin-Related Modifier Proteins
  • TACR1 protein, human
  • Transcription Factors
  • Substance P

Grant support

CONACyT CB2013-220515 and FC-921; PAPIIT/UNAM IN206015 and IN206518 to SCO. Collaboration between UNAM and Pontificia Universidad Católica de Chile was fostered by ICGEB MEX03/06 grant to SCO. CONACyT fellowship was awarded to GZG (255401) and GMH (588372).