FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system

Krishna C. Yalla; Christina Elliott; Jon P. Day; Jane Findlay; Stephen Barratt; Zoë A. Hughes; Lindsay Wilson; E. Whiteley; Michael Popiolek; Yunfeng Li; John Dunlop; Richard Killick; David Roger Adams; Nicholas J. Brandon; Miles Douglas Houslay; Bing Hao; George Scott Baillie

doi:10.1038/mp.2017.138

FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system

Krishna C. Yalla, Christina Elliott, Jon P. Day, Jane Findlay, Stephen Barratt, Zoë A. Hughes, Lindsay Wilson, E. Whiteley, Michael Popiolek, Yunfeng Li, John Dunlop, Richard Killick, David Roger Adams, Nicholas J. Brandon, Miles Douglas Houslay, Bing Hao, George Scott Baillie

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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 the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the FBox 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.

Original language	English
Pages (from-to)	1278–1286
Number of pages	9
Journal	Molecular Psychiatry
Volume	23
Issue number	5
DOIs	https://doi.org/10.1038/mp.2017.138
Publication status	Published - 20 Jul 2017

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David Roger Adams
- D.R.Adamshw.acuk
- School of Engineering & Physical Sciences, Institute of Chemical Sciences - Professor
- School of Engineering & Physical Sciences - Professor
Person: Academic (Research & Teaching)

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Yalla, K. C., 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., & Baillie, G. S. (2017). FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system. Molecular Psychiatry, 23(5), 1278–1286. https://doi.org/10.1038/mp.2017.138

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title = "FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system",

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 the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the FBox 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.",

author = "Yalla, {Krishna C.} and Christina Elliott and Day, {Jon P.} and Jane Findlay and Stephen Barratt and Hughes, {Zo{\"e} A.} and Lindsay Wilson and E. Whiteley and Michael Popiolek and Yunfeng Li and John Dunlop and Richard Killick and Adams, {David Roger} and Brandon, {Nicholas J.} and Houslay, {Miles Douglas} and Bing Hao and Baillie, {George Scott}",

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AU - Wilson, Lindsay

AU - Whiteley, E.

AU - Popiolek, Michael

AU - Li, Yunfeng

AU - Dunlop, John

AU - Killick, Richard

AU - Adams, David Roger

AU - Brandon, Nicholas J.

AU - Houslay, Miles Douglas

AU - Hao, Bing

AU - Baillie, George Scott

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AB - 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 the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the FBox 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.

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FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system

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