title: Nuclear translocation of cellular retinoic acid-binding protein II is regulated by retinoic acid-controlled SUMOylation.
abstract: Cellular retinoic acid-binding protein II (CRABP-II) undergoes nuclear translocation upon binding of retinoic acid (RA). In the nucleus, CRABP-II directly binds to the nuclear receptor RAR to form a complex through which RA is "channeled" from the binding protein to the receptor. CRABP-II thus facilitates the ligation of RAR and markedly enhances its transcriptional activity. The primary sequence of CRABP-II contains three putative SUMOylation sites, centered at K45, K87, and K102. We show here that RA induces interactions of CRABP-II with the E2 SUMO ligase Ubc9 and triggers SUMOylation of the protein both in vitro and in cultured cells. Mutagenesis analyses demonstrate that K102 is the sole CRABP-II residue to be SUMOylated in response to RA. Mutation of this residue abolishes the ability of CRABP-II to undergo nuclear translocation in response RA and thus impairs CRABP-II-mediated activation of RAR. Additional observations demonstrate that apo-CRABP-II is associated with endoplasmic reticulum (ER), and that RA triggers the dissociation of CRABP-II from this location. Furthermore, we show that RA-induced dissociation of CRABP-II from the ER requires SUMOylation of K102. Hence, SUMOylation of K102 in response to RA binding is critical for dissociation of CRABP-II from ER and, consequently, for mobilization of the protein to nucleus and for its cooperation with RAR.
authors: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors: Avijit
authors: A
authors: Majumdar
authors: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors: Anca D
authors: AD
authors: Petrescu
authors: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors: Yin
authors: Y
authors: Xiong
authors: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106. Electronic address: noa.noy@case.edu.
authors: Noa
authors: N
authors: Noy
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D058207:Sumoylation; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9