Phosphorylation of the Retinoid X Receptor at the Omega loop, modulates the expression of retinoic-acid-target genes with a promoter context specificity

The retinoid response is mediated by two classes of nuclear receptors, the retinoic acid receptors (RARα, β, and γ) and the retinoid X receptors (RXRα, β, and γ) which act as ligand-dependent heterodimeric RAR/RXR transcription activators. Like most transcription factors, RARs and RXRs are regulated by phosphorylation processes. Here, we report that stress agents induce RXRα phosphorylation, subsequently to the activation of the stress-activated protein kinases cascade (JNKs). This phosphorylation process concerns three residues located in the N-terminal AF-1 domain of RXRα and one located in the omega loop of the Ligand Binding Domain. To decipher how stress-induced RXRα phosphorylation influences the transcription of RA-target genes, we used a ribotoxic stress agent, anisomycin, which activates signaling kinases without promoting DNA or protein damages, at subinhibitory concentrations. Taking advantage of vectors expressing recombinant RXRα mutated at its phosphorylation sites and of F9 cell lines re-expressing the same RXRα mutants in an RXRα null background, we provide evidence that stress signaling modulates RAR/RXRα-mediated transcription, through the phosphorylation of RXRα at the residue located in the Omega loop, in a promoter context-dependent manner.