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

The Journal of Cell Biology
Sungmin SongYong-Keun Jung

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.

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Citations

Aug 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Hyo-Jin KimYong-Keun Jung
Nov 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Scott D RyanSteffany A L Bennett
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Aug 26, 2014·Cellular and Molecular Life Sciences : CMLS·Tae-In KamYong-Keun Jung
Oct 26, 2010·Cellular and Molecular Life Sciences : CMLS·SangMi ShimYong-Keun Jung
Nov 12, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shu-Xun LiuBo-Lin Zhang
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Dec 4, 2014·Molecular Neurobiology·Min XiaJiaxiang Xiong
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Nov 11, 2016·Evidence-based Complementary and Alternative Medicine : ECAM·Lumei LiuYaming Li
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Methods Mentioned

BETA
immunoprecipitation
ubiquitination
gene trap
gene-trap
PCR
transgenic

Software Mentioned

Elements F
NIS
Photoshop

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