Dear Editor,

Disruption of endoplasmic reticulum (ER) function is associated with numerous human diseases.1, 2 It leads to the initiation of a stress response known as the unfolded protein response, whose initial goal is to resolve the ensuing stress; however, when unable to do so, it induces cell death.3, 4 ER stress-induced cell death has been shown to proceed primarily through apoptosis. It remained unclear whether ER stress is also associated with other forms of cell death. Using bax−/−bak−/− or Bcl-xL-overexpressing cells that are defective in apoptosis, here, we show that prolonged ER stress still results in cell death in a fashion resembling necrosis. This necrosis-like cell death is associated with autophagy. In response to ER stress, autophagy is induced in both wild-type and bax−/−bak−/− cells to a similar extent. Overexpression of wild-type Bax or Bak, as well as ER-targeted Bak does not induce autophagy, indicating that the multi-domain proapoptotic Bcl-2 proteins do not affect autophagy. Inhibition of autophagy results in enhanced cell death in apoptosis-competent cells, but reduced cell death in apoptosis-deficient cells. Thus, in response to ER stress, while autophagy serves as a survival response to delay apoptosis, it promotes cell death by necrosis in cells with impaired apoptosis.

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