The nuclear receptor NR4A1 induces a form of cell death dependent on autophagy in mammalian cells

PLoS One. 2012;7(10):e46422. doi: 10.1371/journal.pone.0046422. Epub 2012 Oct 5.

Abstract

The control of cell death is a biological process essential for proper development, and for preventing devastating pathologies like cancer and neurodegeneration. On the other hand, autophagy regulation is essential for protein and organelle degradation, and its dysfunction is associated with overlapping pathologies like cancer and neurodegeneration, but also for microbial infection and aging. In the present report we show that two evolutionarily unrelated receptors--Neurokinin 1 Receptor (NK(1)R,) a G-protein coupled receptor, and Insulin-like Growth Factor 1 Receptor (IGF1R), a tyrosine kinase receptor--both induce non-apoptotic cell death with autophagic features and requiring the activity of the autophagic core machinery proteins PI3K-III, Beclin-1 and Atg7. Remarkably, this form of cell death occurs in apoptosis-competent cells. The signal transduction pathways engaged by these receptors both converged on the activation of the nuclear receptor NR4A1, which has previously been shown to play a critical role in some paradigms of apoptosis and in NK(1)R-induced cell death. The activity of NR4A1 was necessary for IGF1R-induced cell death, as well as for a canonical model of cell death by autophagy induced by the presence of a pan-caspase inhibitor, suggesting that NR4A1 is a general modulator of this kind of cell death. During cell death by autophagy, NR4A1 was transcriptionally competent, even though a fraction of it was present in the cytoplasm. Interestingly, NR4A1 interacts with the tumor suppressor p53 but not with Beclin-1 complex. Therefore the mechanism to promote cell death by autophagy might involve regulation of gene expression, as well as protein interactions. Understanding the molecular basis of autophagy and cell death mediation by NR4A1, should provide novel insights and targets for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy*
  • Caspase Inhibitors / pharmacology
  • Cell Death / physiology*
  • HEK293 Cells
  • Humans
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / physiology*
  • Receptor, IGF Type 1 / physiology

Substances

  • Caspase Inhibitors
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptor, IGF Type 1

Grant support

This work was supported by CONACyT (Consejo Nacional de Ciencia y Tecnología) grants PQ46174 and P106598 to SCO; PAPIIT-UNAM (Programa de Apoyo a Proyectos de Investigación e Inovación Tecnológica - Universidad Nacional Autónoma de México) grant IN221909 to SCO; and ICGEB (International Center for Genetic Engineering and Biotechnology www.icgeb.org) grant MEX06/03 to SCO. JBR and XG were undergraduate students supported by CONACyT PQ46174; GZG and DAR received fellowship for Master studies from CONACyT (255401 and 48006 respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.