Receptor-interacting protein 140 interacts with and inhibits transactivation by, peroxisome proliferator-activated receptor alpha and liver-X-receptor alpha

Receptor interacting protein 140 (RIP140), a previously identified putative ligand-dependent coactivator of nuclear hormone receptors, was isolated by yeast two-hybrid cloning as a factor that interacts with peroxisome prolif erator-activated receptor alpha (PPAR alpha). This interaction in yeast req uired the integrity of the carboxyl-terminal, ligand-dependent activation d omain of PPAR alpha. However, protein binding studies carried out in vitro showed that full-length RIP140 bound efficiently to PPAR alpha in the absen ce of exogenously added ligand. RIP140 also bound strongly to the liver-X-r eceptor (LXR alpha) in the absence of an activator for this receptor. In co ntrast, a strong interaction of RIP140 with the PPAR alpha and LXR alpha he terodimerization partner retinoid-X-receptor alpha (RXR alpha) required the presence of its cognate ligand, 9-cis retinoic acid. Transfection analysis in mammalian cells demonstrated that RIP140 antagonized PPAR alpha/RXR alp ha- and LXR alpha/RXR alpha-mediated signaling. Our findings identify RIP14 0 as a novel modulator of transcriptional activation mediated by PPAR alpha and LXR alpha and indicate that RIP140 can also bind to nuclear hormone re ceptors in a ligand-independent manner and repress their activity. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.