title: Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia.
abstract: A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia-ischemia in vivo. A chemical screen of ~5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na(+),K(+)-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na(+),K(+)-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na(+),K(+)-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.
authors.affiliation: Center for Autophagy Research, Departments of Internal Medicine, Biochemistry, and Microbiology, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Sanae
authors.initials: S
authors.lastname: Shoji-Kawata
authors.forename: Rhea M
authors.initials: RM
authors.lastname: Sumpter
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ginet
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: Bruce
authors.initials: B
authors.lastname: Posner
authors.forename: Khoa A
authors.initials: KA
authors.lastname: Tran
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Stanley Y
authors.initials: SY
authors.lastname: Shaw
authors.forename: Peter G H
authors.initials: PG
authors.lastname: Clarke
authors.forename: Julien
authors.initials: J
authors.lastname: Puyal
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002301:Cardiac Glycosides / Q000494:pharmacology; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002301:Cardiac Glycosides; D057846:Cell-Penetrating Peptides; D009419:Nerve Tissue Proteins; D000254:Sodium-Potassium-Exchanging ATPase