E3 Ligase STUB1/CHIP Regulates NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Accumulation in Aged Brain, a Process Impaired in Certain Alzheimer Disease Patients

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme that is important in maintaining the cellular redox state and regulating protein degradation. The NQO1 polymorphism C609T has been associated with increased susceptibility to various age-related pathologies. We show here that NQO1 protein leve...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-03, Vol.286 (11), p.8839-8845
Main Authors: Tsvetkov, Peter, Adamovich, Yaarit, Elliott, Evan, Shaul, Yosef
Format: Article
Language:English
Subjects:
Aging
Aging - genetics
Aging - metabolism
Alzheimer Disease
Alzheimer Disease - enzymology
Alzheimer Disease - genetics
C Terminus of HSC70-interacting Protein
C609T NQO1 Polymorphism
E3 Ubiquitin Ligase
Genetic Polymorphism
HEK293 Cells
Hippocampus - enzymology
HSC70 Heat-Shock Proteins - genetics
HSC70 Heat-Shock Proteins - metabolism
Humans
NAD(P)H Dehydrogenase (Quinone) - genetics
NAD(P)H Dehydrogenase (Quinone) - metabolism
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
NQO1
Polymorphism, Genetic
Proteasome
Protein Degradation
Protein Synthesis and Degradation
STUB1
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination - genetics
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Summary:NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme that is important in maintaining the cellular redox state and regulating protein degradation. The NQO1 polymorphism C609T has been associated with increased susceptibility to various age-related pathologies. We show here that NQO1 protein level is regulated by the E3 ligase STUB1/CHIP (C terminus of Hsc70-interacting protein). NQO1 binds STUB1 via the Hsc70-interacting domain (tetratricopeptide repeat domain) and undergoes ubiquitination and degradation. We demonstrate here that the product of the C609T polymorphism (P187S) is a stronger STUB1 interactor with increased susceptibility to ubiquitination by the E3 ligase STUB1. Furthermore, age-dependent decrease of STUB1 correlates with increased NQO1 accumulation. Remarkably, examination of hippocampi from Alzheimer disease patients revealed that in half of the cases examined the NQO1 protein level was undetectable due to C609T polymorphism, suggesting that the age-dependent accumulation of NQO1 is impaired in certain Alzheimer disease patients.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.193276