Phosphorylation and transcriptional activity regulation of retinoid-related orphan receptor alpha 1 by protein kinases C

Retinoid-related orphan receptor alpha 1 (ROR alpha 1) is a member of the nuclear receptor superfamily. It is highly expressed in CNS particularly in the cerebellum. Absence of this transcription factor in mice leads to several abnormalities, such as cerebellar atrophy linked to Purkinje cell death and impaired differentiation. A major role of ROR alpha 1 in neuronal survival is the control of reactive oxygen species homeostasis. ROR alpha 1 is a constitutively active receptor, but its regulation is yet not well known. Protein kinase C (PKC) also plays a major role in neuronal survival and differentiation, suggesting its possible involvement in post-translational modifications and regulation of ROR alpha 1 transcriptional activity. To test this hypothesis, we over-expressed the human isoform of this nuclear receptor in cortical neurons and COS-7 cells, which were then treated with different effectors acting on PKC activity. We showed for the first time that conventional PKCs induce phosphorylation and inhibition of ROR alpha 1 activity. We also investigated mito-gen-activated protein kinase/extracellular signal-regulated kinase (1/2) involvement in this effect. Our results bring new insights into the control of ROR alpha 1 activity and highlight its importance in further investigations of the mechanisms involved in neuronal cell death in neurodegenerative diseases.