1. E2-25K/Hip-2 regulates caspase-12 in ER stress–mediated Aβ neurotoxicity
- Author
-
Jee-Yeon Noh, Joo Yong Lee, Tae In Kam, Huikyong Lee, Toshiyuki Nakagawa, Soo Jung Seo, Young-Yun Kong, Yong-Keun Jung, Deog-Young Choi, Hammou Oubrahim, Sang Mi Shim, Chul Woong Chung, Mei Ling Tai, and Sungmin Song
- Subjects
Protein Folding ,Neurotoxins ,Down-Regulation ,Endoplasmic Reticulum ,Models, Biological ,Article ,Cell Line ,Mice ,Enzyme activator ,Ubiquitin ,Enzyme Stability ,medicine ,Animals ,Humans ,Caspase 12 ,Research Articles ,Caspase ,Cerebral Cortex ,Neurons ,Amyloid beta-Peptides ,Cell Death ,biology ,Calpain ,Endoplasmic reticulum ,Neurotoxicity ,Cell Biology ,medicine.disease ,Rats ,Cell biology ,Enzyme Activation ,Proteasome ,Enzyme Induction ,Ubiquitin-Conjugating Enzymes ,biology.protein ,Unfolded protein response ,Reactive Oxygen Species - Abstract
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.
- Published
- 2008