Abstract
Damage to endoplasmic reticulum (ER) homeostasis that cannot be corrected by the unfolded protein response activates cell death. Here, we identified death-associated protein kinase (DAPk) as an important component in the ER stress-induced cell death pathway. DAPk-/- mice are protected from kidney damage caused by injection of the ER stress-inducer tunicamycin. Likewise, the cell death response to ER stress-inducers is reduced in DAPk-/- primary fibroblasts. Both caspase activation and autophagy induction, events that are activated by ER stress and precede cell death, are significantly attenuated in the DAPk null cells. Notably, in this cellular setting, autophagy serves as a second cell killing mechanism that acts in concert with apoptosis, as the depletion of Atg5 or Beclin1 from fibroblasts significantly protected from ER stress-induced death when combined with caspase-3 depletion. We further show that ER stress promotes the catalytic activity of DAPk by causing dephosphorylation of an inhibitory autophosphorylation on Ser308 by a PP2A-like phosphatase. Thus, DAPk constitutes a critical integration point in ER stress signaling, transmitting these signals into two distinct directions, caspase activation and autophagy, leading to cell death.
| Original language | English |
|---|---|
| Pages (from-to) | 1875-1886 |
| Number of pages | 12 |
| Journal | Cell Death and Differentiation |
| Volume | 15 |
| Issue number | 12 |
| DOIs | |
| State | Published - 2008 |
| Externally published | Yes |
Bibliographical note
Funding Information:Acknowledgements. We thank Mitsubishi Chemical Corporation (Japan) for critical technical help in the generation of the DAPk−/− mice, Hanna Berissi for technical assistance during the production and testing of anti-phosphoserine308 antibodies, and Sharon Reef for reading the manuscript and fruitful discussions. We also thank Rony Seger (Weizmann Institute of Science) for generously providing anti-JNK and anti-phospho-JNK antibodies, and Atan Gross (Weizmann Institute of Science) for generously providing Bax/Bak−/−, caspase-3−/− and + / + fibroblasts. The electron microscopy studies were conducted at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. This study was supported by the Israel Science Foundation administered by the Israel Academy of Sciences and Humanities and by the Kahn Fund for System Biology at the Weizmann Institute of Science. AK is the incumbent of Helena Rubinstein Chair of Cancer Research.
Funding
Acknowledgements. We thank Mitsubishi Chemical Corporation (Japan) for critical technical help in the generation of the DAPk−/− mice, Hanna Berissi for technical assistance during the production and testing of anti-phosphoserine308 antibodies, and Sharon Reef for reading the manuscript and fruitful discussions. We also thank Rony Seger (Weizmann Institute of Science) for generously providing anti-JNK and anti-phospho-JNK antibodies, and Atan Gross (Weizmann Institute of Science) for generously providing Bax/Bak−/−, caspase-3−/− and + / + fibroblasts. The electron microscopy studies were conducted at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. This study was supported by the Israel Science Foundation administered by the Israel Academy of Sciences and Humanities and by the Kahn Fund for System Biology at the Weizmann Institute of Science. AK is the incumbent of Helena Rubinstein Chair of Cancer Research.
| Funders |
|---|
| Weizmann Institute of Science |
| Israel Academy of Sciences and Humanities |
| Israel Science Foundation |