Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity.
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.
Song
Sungmin
S
Department of Life Science, Kwangju Institute of Science and Technology, Kwangju 500-712, South Korea.
Kim
So-Young
SY
Hong
Yeon-Mi
YM
Jo
Dong-Gyu
DG
Lee
Joo-Yong
JY
Shim
Sang Mi
SM
Chung
Chul-Woong
CW
Seo
Soo Jung
SJ
Yoo
Yung Joon
YJ
Koh
Jae-Young
JY
Lee
Min Chul
MC
Yates
Allan J
AJ
Ichijo
Hidenori
H
Jung
Yong-Keun
YK
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*
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