Regulation of transcriptional activity of RORα by AMPK-induced phosphorylation

Abstract

Retinoic acid receptor-related orphan receptor α (RORα) is a member of the steroid/thyroid hormone receptor superfamily and plays important roles in various metabolic pathways by regulating the expression of many metabolic genes. Previous study has shown that AMP-activated protein kinase (AMPK) induces the phosphorylation of RORα in vitro. To investigate the contribution of AMPK-induced phosphorylation to RORα function, a substitution of serine 139 for alanine, which is unable to be phosphorylated by AMPK, was performed. I examined the transcriptional activity using the RORE-luc reporter system and found that both types of RORα demonstrate similar activity. Next, in order to identify AMPK-specific responsiveness, I tested the activity change using myc-CA-AMPK (the myc-tagged constitutively active form of AMPK). Interestingly, I found that only the wild type showed increased activity by CA-AMPK cotransfection. After that, I produced GFP-tagged RORα and RORα-S139A and observed that both types existed in the nucleus and that there was no change in cellular localization after AICAR (a selective AMPK activator) treatment. Then I measured the mRNA expression of glucose-6-phosphatase, one of the target genes of RORα

I found that AMPK increased the expression of glucose-6-phosphatase and that the increase was diminished by the AMPK inhibitor, Compound C. Together, these results suggest that the phosphorylation of RORα has an impact on the biochemical function of the receptor

further study is needed to clarify the physiological importance of this finding.