E2-25K/Hip-2 regulates caspase-12 in ER stress-mediated Abeta neurotoxicity.
Amyloid-beta (Abeta) neurotoxicity is believed to contribute to the pathogenesis of Alzheimer's disease (AD). Previously we found that E2-25K/Hip-2, an E2 ubiquitin-conjugating enzyme, mediates Abeta neurotoxicity. Here, we report that E2-25K/Hip-2 modulates caspase-12 activity via the ubiquitin/proteasome system. Levels of endoplasmic reticulum (ER)-resident caspase-12 are strongly up-regulated in the brains of AD model mice, where the enzyme colocalizes with E2-25K/Hip-2. Abeta increases expression of E2-25K/Hip-2, which then stabilizes caspase-12 protein by inhibiting proteasome activity. This increase in E2-25K/Hip-2 also induces proteolytic activation of caspase-12 through its ability to induce calpainlike activity. Knockdown of E2-25K/Hip-2 expression suppresses neuronal cell death triggered by ER stress, and thus caspase-12 is required for the E2-25K/Hip-2-mediated cell death. Finally, we find that E2-25K/Hip-2-deficient cortical neurons are resistant to Abeta toxicity and to the induction of ER stress and caspase-12 expression by Abeta. E2-25K/Hip-2 is thus an essential upstream regulator of the expression and activation of caspase-12 in ER stress-mediated Abeta neurotoxicity.
Song
Sungmin
S
School of Biological Sciences, Seoul National University, Seoul, Korea.
Lee
Huikyong
H
Kam
Tae-In
TI
Tai
Mei Ling
ML
Lee
Joo-Yong
JY
Noh
Jee-Yeon
JY
Shim
Sang Mi
SM
Seo
Soo Jung
SJ
Kong
Young-Yun
YY
Nakagawa
Toshiyuki
T
Chung
Chul-Woong
CW
Choi
Deog-Young
DY
Oubrahim
Hammou
H
Jung
Yong-Keun
YK
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D053454:Caspase 12 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009498:Neurotoxins / Q000633:toxicity*; D017510:Protein Folding; D051381:Rats; D017382:Reactive Oxygen Species / Q000494:pharmacology; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D017382:Reactive Oxygen Species; C531382:Ube2k protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D002154:Calpain; D053454:Caspase 12