Ligand-dependent nucleo-cytoplasmic shuttling of peroxisome proliferator-activated receptors,  PPARα  and  PPARγ.
Peroxisome proliferator-activated receptors (PPARs) play important roles in diverse biological processes including metabolisms of sugars and lipids and differentiation of cells such as adipocytes. PPARs are transcription factors belonging to the ligand-dependent hormone receptor group. To function as transcription factors, PPARs translocate into nucleus where they associate with transcription apparatus. However, mechanisms underlying nuclear transport of PPARs remain enigmatic. We show here that PPARα and PPARγ dynamically shuttle between nucleus and cytoplasm, although they constitutively and predominantly appear in nucleus. With a series of truncation mutants, we identify that PPAR nuclear transport is mediated by at least two nuclear localization signals (NLSs) in DNA-binding domain (DBD)-hinge and activation function 1 (AF1) regions and their respective receptors including importinα/β, importin 7, and an unidentified receptor. PPARs also harbor two nuclear export signals in DBD and ligand-binding domain regions that are recognized by distinct export receptors, calreticulin and CRM1. Moreover, we show that nuclear-cytoplasmic shuttling of PPARs is regulated by respective PPAR ligands and Ca2+ concentration. Taken together, we suggest that the multiple pathways for the nuclear-cytoplasmic transport of PPARs regulate the biological functions of PPARs in response to external signals.
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan.
Tomoe
T
Umemoto
Yukio
Y
Fujiki
D000818:Animals; D037282:Calreticulin / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000378:metabolism; D047493:PPAR alpha / Q000737:chemistry / Q000378:metabolism*; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D028901:alpha Karyopherins / Q000378:metabolism; D000097606:Exportin 1 Protein
D037282:Calreticulin; D028884:Karyopherins; D008024:Ligands; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D047493:PPAR alpha; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D028901:alpha Karyopherins; D000097606:Exportin 1 Protein