Chen T, Laurenzana EM, Coslo DM, Chen F, Omiecinski CJ

The constitutive androstane receptor (CAR; NR1I3) is a critical xenobiotic sensor that regulates xenobiotic metabolism, drug clearance, energy and lipid homeostasis, cell proliferation and development. Although constitutively active, in hepatocytes CAR is normally held quiescent through a tethering mechanism in the cytosol, anchored to a protein complex that includes several ...

Read More

components, including heat shock protein 90. Release and subsequent nuclear translocation of CAR is triggered through either direct binding to ligand activators such as 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), or through indirect chemical activation, such as with phenobarbital (PB). In this study, we demonstrate that proteasomal inhibition markedly disrupts CAR function, repressing CAR nuclear trafficking, disrupting CAR's interaction with nuclear co-activators and inhibiting induction of CAR target gene responses in human primary hepatocytes following treatment with either PB or CITCO. Paradoxically, these effects occur following accumulation of ubiquitinated hCAR and its interaction with the SUG1 subunit of the 26S proteasome. Together, these data demonstrate that the proteasome complex functions at multiple levels to regulate the functional biology of hCAR activity.

Date: Nov. 14, 2013

View in: Pubmed Google Scholar

161766