The mechanism whereby heat shock induces apoptosis depends on the innate sensitivity of cells to stress
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The cellular response to heat shock (HS) is a paradigm for many human diseases collectively known as “protein conformation diseases” in which the accumulation of misfolded proteins induces cell death. Here, we analyzed how cells having a different apoptotic threshold die subsequent to a treatment with HS. Cells with a low apoptotic threshold mainly induced apoptosis through activation of conventional stress kinase signaling pathways. By contrast, cells with a high apoptotic threshold also died by apoptosis but likely after the accumulation of heat-aggregated proteins as revealed by the formation of aggresomes in these cells, which were associated with the generation of atypical nuclear deformations. Inhibition of the proteasome or expression of an aggregation prone protein produced similar nuclear alterations. Furthermore, elevated levels of chaperones markedly suppressed both HS-induced nuclear deformations and apoptosis induced upon protein aggregation whereas they had little effect on stress kinase-mediated apoptosis. We conclude that the relative contribution of stress signaling pathways and the accumulation of protein aggregates to cell death by apoptosis is related to the innate sensitivity of cells to deadly insults.
KeywordsApoptosis Aggresome Heat shock Huntingtin Nuclei morphology Proteasome
We thank R.J. Youle, D. Baltimore, R.D. Goldman, P.Y. Perche, D.C. Rubinsztein, and R.R. Kopito for their generous contribution of reagents. This study was supported by the Canadian Institutes of Health Research Grant MOP-7088 and the Canada Research Chair in Stress Signal Transduction.
Movie of Rat1-control cells expressing H2A-GFP after HS treatment. Rat1-control cells were transfected with H2A-GFP and then heated for 45 min at 43.5°C before their analysis by live imaging. The movie starts 1 h after HS treatment and covers a period of 24 h post-HS (one image every 30 min). All the nuclei present a deformed morphology. Two apoptotic events occur (one in the middle of the field and a second in the top right of the field after a cell division). (MOV 2355 kb)
Movie of Rat1-myc cells expressing H2A-GFP after HS treatment. Rat1-myc cells were transfected with H2A-GFP and then heated for 45 min at 43.5°C before their analysis by live imaging. The movie starts 1 h after HS treatment and covers a period of 24 h post-HS (one image every 30 min). All the nuclei present a deformed morphology and then the cells die by apoptosis. (MOV 1197 kb)
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