FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system

Yalla, K. et al. (2018) FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system. Molecular Psychiatry, 23(5), pp. 1278-1286. (doi:10.1038/mp.2017.138) (PMID:28727686)

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Abstract

Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Findlay, Mrs Jane and Elliott, Dr Christina and Baillie, Professor George and WHITELEY, Ellanor and Day, Dr Jonathan and Yalla, Dr Krishna
Authors: Yalla, K., Elliott, C., Day, J.P., Findlay, J., Barratt, S., Hughes, Z.A., Wilson, L., Whiteley, E., Popiolek, M., Li, Y., Dunlop, J., Killick, R., Adams, D.R., Brandon, N.J., Houslay, M.D., Hao, B., and Baillie, G.S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Molecular Psychiatry
Publisher:Nature Publishing Group
ISSN:1359-4184
ISSN (Online):1476-5578
Published Online:20 July 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Molecular Psychiatry 23(5):1278-1286
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES