title: GSK-3-mediated phosphorylation couples ER-Golgi transport and nuclear stabilization of the CREB-H transcription factor to mediate apolipoprotein secretion.
abstract: CREB-H, an ER-anchored transcription factor, plays a key role in regulating secretion in metabolic pathways, particularly triglyceride homeostasis. It controls the production both of secretory pathway components and cargoes, including apolipoproteins ApoA-IV and ApoC-II, contributing to VLDL/HDL distribution and lipolysis. The key mechanism controlling CREB-H activity involves its ER retention and forward transport to the Golgi, where it is cleaved by Golgi-resident proteases, releasing the N-terminal product, which traffics to the nucleus to effect transcriptional responses. Here we show that a serine-rich motif termed the P-motif, located in the N-terminus between serines 73 and 90, controls release of the precursor transmembrane form from the ER and its forward transport to the Golgi. This motif is subject to GSK-3 phosphorylation, promoting ER retention, while mutation of target serines and drug inhibition of GSK-3 activity coordinately induce both forward transport of the precursor and cleavage, resulting in nuclear import. We previously showed that for the nuclear product, the P-motif is subject to multiple phosphorylations, which regulate stability by targeting the protein to the SCFFbw1aE3 ubiquitin ligase. Thus phosphorylation at the P-motif provides integrated control of CREB-H function, coupling intercompartmental transport in the cytoplasm with stabilization of the active form in the nucleus.
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, United Kingdom.
authors.forename: Sónia
authors.initials: S
authors.lastname: Barbosa
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Carreira
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, United Kingdom pohare@imperial.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Hare
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D001054:Apolipoproteins A; D019556:COS Cells; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008066:Lipolysis; D010766:Phosphorylation; D055571:Secretory Pathway; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001053:Apolipoproteins; D001054:Apolipoproteins A; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; C022205:apolipoprotein A-IV; D038362:Glycogen Synthase Kinase 3