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A caspase for stress

siRNA of caspase-4 (right) prevents most cell death after ER stress.

Stress in the endoplasmic reticulum (ER)—caused by anything from ischemia to expression of mutant proteins—triggers several responses. Cells slow translation, produce more chaperones, degrade more unfolded proteins, and as a last resort, induce apoptosis. Hitomi et al. (page 347) identify caspase-4 as a critical component of the pathway leading from ER stress to apoptosis, specifically after the expression of cytotoxic Aß from Alzheimer's patients.

Caspase-12 has already been identified as mediating such a function in mice, but the caspase-12 gene in humans has frame-shifts and a premature stop codon. Hitomi et al. therefore screened cDNA libraries with mouse caspase-12 and came up with human caspase-4. Although some caspase-4 is found on mitochondria, the protein is also found on the ER, and its cleavage after ER stress or incubation with Aß is not prevented by overexpression of mitochondrial Bcl-2.

Removal of caspase-4 with siRNA halved cell death after ER stress in neuroblastoma cells and reduced cell death by two thirds after Aß treatment. But the incomplete suppression, especially in other cell lines, suggests that other caspases may share this responsibility. Sorting out possible contributions by caspase-2 and caspase-5 will be important before caspase-based therapy is attempted for Alzheimer's.

William A. Wells

wellsw{at}rockefeller.edu

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Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aß-induced cell death

Junichi Hitomi, Taiichi Katayama, Yutaka Eguchi, Takashi Kudo, Manabu Taniguchi, Yoshihisa Koyama, Takayuki Manabe, Satoru Yamagishi, Yoshio Bando, Kazunori Imaizumi, Yoshihide Tsujimoto, and Masaya Tohyama
J. Cell Biol. 2004 165: 347-356. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 618K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Related Collections Related Article Social Bookmarking                            What's this?