title: Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity.
abstract: The ubiquitin/proteasome system has been proposed to play an important role in Alzheimer's disease (AD) pathogenesis. However, the critical factor(s) modulating both amyloid-beta peptide (Abeta) neurotoxicity and ubiquitin/proteasome system in AD are not known. We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity. The expression of E2-25K/Hip-2 was upregulated in the neurons exposed to Abeta(1-42) in vivo and in culture. Enzymatic activity of E2-25K/Hip-2 was required for both Abeta(1-42) neurotoxicity and inhibition of proteasome activity. E2-25K/Hip-2 functioned upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta(1-42) toxicity. Further, the ubiquitin mutant, UBB+1, a potent inhibitor of the proteasome which is found in Alzheimer's brains, was colocalized and functionally interacted with E2-25K/Hip-2 in mediating neurotoxicity. These results suggest that E2-25K/Hip-2 is a crucial factor in regulating Abeta neurotoxicity and could play a role in the pathogenesis of Alzheimer's disease.
authors.affiliation: Department of Life Science, Kwangju Institute of Science and Technology, Kwangju 500-712, South Korea.
authors.forename: Sungmin
authors.initials: S
authors.lastname: Song
authors.forename: So-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Yeon-Mi
authors.initials: YM
authors.lastname: Hong
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shim
authors.forename: Chul-Woong
authors.initials: CW
authors.lastname: Chung
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Seo
authors.forename: Yung Joon
authors.initials: YJ
authors.lastname: Yoo
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.forename: Min Chul
authors.initials: MC
authors.lastname: Lee
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Yates
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005260:Female; D005333:Fetus; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D025801:Ubiquitin; C075222:amyloid beta-protein (1-42); C100879:UBE2K protein, human; D044763:Ubiquitin-Conjugating Enzymes; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases