title: E3 ligase STUB1/CHIP regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) accumulation in aged brain, a process impaired in certain Alzheimer disease patients.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Peter
authors.initials: P
authors.lastname: Tsvetkov
authors.forename: Yaarit
authors.initials: Y
authors.lastname: Adamovich
authors.forename: Evan
authors.initials: E
authors.lastname: Elliott
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shaul
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D009419:Nerve Tissue Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases