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Published online August 18, 2008
doi:10.1083/jcb.200711066
The Journal of Cell Biology, Vol. 182, No. 4, 675-684
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Song et al.
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Article

 E2-25K/Hip-2 regulates caspase-12 in ER stress–mediated Aβ neurotoxicity

Sungmin Song1, Huikyong Lee1, Tae-In Kam1, Mei Ling Tai1, Joo-Yong Lee2, Jee-Yeon Noh1, Sang Mi Shim1, Soo Jung Seo1, Young-Yun Kong3, Toshiyuki Nakagawa4, Chul-Woong Chung5, Deog-Young Choi5, Hammou Oubrahim6, and Yong-Keun Jung1

1 School of Biological Sciences, Seoul National University, Seoul 151-747, Korea
2 University of Ulsan College of Medicine, Seoul 138-736, Korea
3 Pohang University of Science and Technology, Pohang 790-784, Korea
4 Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
5 LG Life Science Research Park, Taejon 305-389, Korea
6 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Correspondence to Yong-Keun Jung: ykjung{at}snu.ac.kr

Amyloid-β (Aβ) 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 Aβ 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. Aβ 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 Aβ toxicity and to the induction of ER stress and caspase-12 expression by Aβ. E2-25K/Hip-2 is thus an essential upstream regulator of the expression and activation of caspase-12 in ER stress–mediated Aβ neurotoxicity.

Abbreviations used in this paper: AD, Alzheimer's disease; Aβ, amyloid-β; APP, Aβ precursor protein; β-gal, β-galactosidase; KD, knockdown; MEF, mouse embryonic fibroblast; PS1, presenilin 1; ROS, reactive oxygen species; UPS, ubiquitin/proteasome system.


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