Barbosa, S., Carreira, S., O'Hare, P. (2017) GSK-3-mediated phosphorylation couples ER-Golgi transport and nuclear stabilization of the CREB-H transcription factor to mediate apolipoprotein secretion. MOLECULAR BIOLOGY OF THE CELL, 28 (11). pp. 1565-1579. ISSN 1059-1524

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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 SCFFbw1a E3 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.

Item Type:	Article
All Authors:	Barbosa, S., Carreira, S., O'Hare, P.
Additional Information:	ISI Document Delivery No.: EW2MJ Times Cited: 0 Cited Reference Count: 64 Barbosa, Sonia Carreira, Suzanne O'Hare, Peter Medical Research Council [MR/K017926/1] This work was supported by the Medical Research Council, MR/K017926/1. 0 1 AMER SOC CELL BIOLOGY BETHESDA MOL BIOL CELL
Uncontrolled Keywords:	ENDOPLASMIC-RETICULUM STRESS REGULATED INTRAMEMBRANE PROTEOLYSIS UNFOLDED PROTEIN RESPONSE ELEMENT-BINDING PROTEIN FATTY-ACID SYNTHESIS TRIGLYCERIDE-METABOLISM CHOLESTEROL HOMEOSTASIS HEPATIC GLUCONEOGENESIS LIPID HOMEOSTASIS TRANSDUCER OASIS
Research teams:	ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers
Depositing User:	Barry Jenkins
Date Deposited:	07 Jul 2017 15:19
Last Modified:	07 Jul 2017 15:19
URI:	http://publications.icr.ac.uk/id/eprint/16015

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