E2-25K/Hip-2 regulates caspase-12 in ER stress–mediated Aβ neurotoxicity
| Autor: | 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, Sungmin Song |
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| Rok vydání: | 2008 |
| Předmět: |
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 |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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