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

Sungmin Song, Huikyong Lee, Tae In Kam, Ling Tai Mei, Joo Yong Lee, Jee Yeon Noh, Mi Shim Sang, Jung Seo Soo, Young Yun Kong, Toshiyuki Nakagawa, Chul Woong Chung, Deog Young Choi, Hammou Oubrahim, Yong Keun Jung

Research output: Contribution to journalArticle

Abstract

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 calpain-like 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.

Original languageEnglish (US)
Pages (from-to)675-684
Number of pages10
JournalJournal of Cell Biology
Volume182
Issue number4
DOIs
StatePublished - Aug 25 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Song, S., Lee, H., Kam, T. I., Mei, L. T., Lee, J. Y., Noh, J. Y., Sang, M. S., Soo, J. S., Kong, Y. Y., Nakagawa, T., Chung, C. W., Choi, D. Y., Oubrahim, H., & Jung, Y. K. (2008). E2-25K/Hip-2 regulates caspase-12 in ER stress-mediated Aβ neurotoxicity. Journal of Cell Biology, 182(4), 675-684. https://doi.org/10.1083/jcb.200711066