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First published online December 22, 2004
doi: 10.1242/10.1242/jcs.01600

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Activity and subcellular compartmentalization of peroxisome proliferator-activated receptor are altered by the centrosome-associated protein CAP350

¹ Department of Biochemistry, McMaster University, Hamilton, ON L8N 3Z5, Canada
² Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada

^* Author for correspondence (e-mail: rick.rachubinski{at}ualberta.ca)

Accepted 19 October 2004

Peroxisome proliferator-activated nuclear hormone receptors (PPAR) are ligand-activated transcription factors that play pivotal roles in governing metabolic homeostasis and cell growth. PPARs are primarily in the nucleus but, under certain circumstances, can be found in the cytoplasm. We show here that PPAR interacts with the centrosome-associated protein CAP350. CAP350 also interacts with PPAR, PPAR and liver-X-receptor , but not with the 9-cis retinoic acid receptor, RXR. Immunofluorescence analysis indicated that PPAR is diffusely distributed in the nucleus and excluded from the cytoplasm. However, in the presence of coexpressed CAP350, PPAR colocalizes with CAP350 to discrete nuclear foci and to the centrosome, perinuclear region and intermediate filaments. In contrast, the subcellular distribution of RXR or of thyroid hormone receptor was not altered by coexpression of CAP350. An amino-terminal fragment of CAP350 was localized exclusively to nuclear foci and was sufficient to recruit PPAR to these sites. Mutation of the single putative nuclear hormone receptor interacting signature motif LXXLL present in this fragment had no effect on its subnuclear localization but abrogated recruitment of PPAR to nuclear foci. Surprisingly, mutation of the LXXLL motif in this CAP350 subfragment did not prevent its binding to PPAR in vitro, suggesting that this motif serves some function other than PPAR binding in recruiting PPAR to nuclear spots. CAP350 inhibited PPAR-mediated transactivation in an LXXLL-dependent manner, suggesting that CAP350 represses PPAR function. Our findings implicate CAP350 in a dynamic process that recruits PPAR to discrete nuclear and cytoplasmic compartments and suggest that altered intracellular compartmentalization represents a regulatory process that modulates PPAR function.

Key words: PPAR, Nuclear hormone receptors, Intracellular localization, Immunofluorescence, Transactivation

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