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PPP1R16A, The Membrane Subunit of Protein Phosphatase 1β, Signals Nuclear Translocation of the Nuclear Receptor Constitutive Active/Androstane Receptor

Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Constitutive active/androstane receptor (CAR), a member of the nuclear steroid/thyroid hormone receptor family, activates transcription of numerous hepatic genes upon exposure to therapeutic drugs and environmental pollutants. Sequestered in the cytoplasm, this receptor signals xenobiotic exposure, such as phenobarbital (PB), by translocating into the nucleus. Unlike other hormone receptors, translocation can be triggered indirectly without binding to xenobiotics. We have now identified a membrane-associated subunit of protein phosphatase 1 (PPP1R16A, or abbreviated as R16A) as a novel CAR-binding protein. When CAR and R16A are coexpressed in mouse liver, CAR translocates into the nucleus. Close association of R16A and CAR molecule on liver membrane was shown by fluorescence resonance energy transfer (FRET) analysis using expressed yellow fluorescent protein (YFP)-CAR and CFP-R16A fusion proteins. R16A can form dimer through its middle region, where protein kinase A phosphorylation sites are recently identified. Translocation of CAR by R16A correlates with the ability of R16A to form an intermolecular interaction via the middle region. Moreover, this interaction is enhanced by PB treatment in mouse liver. R16A specifically interacted with PP1β in HepG2 cells despite the highly conserved structure of PP1 family molecules. PP1β activity was inhibited by R16A in vitro and coexpression of PP1β in liver can prevent YFP-CAR translocation into mouse liver. Taken together, R16A at the membrane may mediate the PB signal to initiate CAR nuclear translocation, through a mechanism including its dimerization and inhibition of PP1β activity, providing a novel model for the translocation of nuclear receptors in which direct interaction of ligands and the receptors may not be crucial.

Address correspondence to: Dr. Tatsuya Sueyoshi, Pharmacogenetics section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail: sueyoshi{at}niehs.nih.gov