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

J Cell Biol. 2008 Aug 25;182(4):675-84. doi: 10.1083/jcb.200711066. Epub 2008 Aug 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Calpain / metabolism
  • Caspase 12 / biosynthesis
  • Caspase 12 / chemistry
  • Caspase 12 / metabolism*
  • Cell Death / drug effects
  • Cell Line
  • Cerebral Cortex / cytology
  • Cerebral Cortex / enzymology
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / enzymology*
  • Endoplasmic Reticulum / pathology*
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Enzyme Stability / drug effects
  • Humans
  • Mice
  • Models, Biological
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurotoxins / toxicity*
  • Protein Folding
  • Rats
  • Reactive Oxygen Species / pharmacology
  • Ubiquitin-Conjugating Enzymes / metabolism*

Substances

  • Amyloid beta-Peptides
  • Neurotoxins
  • Reactive Oxygen Species
  • Ube2k protein, mouse
  • Ubiquitin-Conjugating Enzymes
  • Calpain
  • Caspase 12