The Nuclear Receptor NR4A1 Induces a Form of Cell Death Dependent on Autophagy in Mammalian Cells

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 (NK1R,) 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 NK1R-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.

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

“…Once released, SP may have direct post-synaptic actions as a neurotransmitter, modulatory function at post-synaptic sites, or other functions on nonneuronal targets 11,14 . The major pathways activated by the SP/NK1R complex lead to phosphoinositide hydrolysis, calcium mobilization, and mitogen-activated protein kinase (MAPK) activation 15,16 . These pathways are involved in neuroinflammation, neuronal excitation, cell survival and cell migration 14,17,18 .…”

Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung

“…Although it has been shown in a transformed cell line (HEK293) that NK-1R acts through Nur77 to induce nonapoptotic cell death with autophagic features (8), paradoxically NK-1R has also been shown in multiple cell lines to induce cell proliferation through transactivation of epidermal growth factor receptor via a metalloproteinase-dependent pathway (25).…”

Calcium-dependent Nr4a1 expression in mouse Leydig cells requires distinct AP1/CRE and MEF2 elements

“…This strategy not only helps the cell conserve energy but also avoids the initiation of any cellular process that might alter the cell basal physiology, like differentiation and steroidogenesis (Martin et al 2008, Maruoka et al 2010, or cause cell death [(Bouzas-Rodriguez et al 2012) and reviewed in (Deutsch et al 2012)]. As MEF2 is associated with co-repressors such as HDACs on the Nr4a1 gene promoter in unstimulated cells, it indirectly prevents unnecessary cellular processes to take place.…”