title: DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death.
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 Ser(308) 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.
authors.affiliation: Department of Molecular Genetics, Rehovot 76100, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Gozuacik
authors.forename: S
authors.initials: S
authors.lastname: Bialik
authors.forename: T
authors.initials: T
authors.lastname: Raveh
authors.forename: G
authors.initials: G
authors.lastname: Mitou
authors.forename: G
authors.initials: G
authors.lastname: Shohat
authors.forename: H
authors.initials: H
authors.lastname: Sabanay
authors.forename: N
authors.initials: N
authors.lastname: Mizushima
authors.forename: T
authors.initials: T
authors.lastname: Yoshimori
authors.forename: A
authors.initials: A
authors.lastname: Kimchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D064550:Death-Associated Protein Kinases; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010768:Phosphoserine / Q000378:metabolism; D014415:Tunicamycin / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D051017:Apoptosis Regulatory Proteins; D014415:Tunicamycin; D010768:Phosphoserine; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020169:Caspases