Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia

Yang Liu, Sanae Shoji-Kawata, Rhea M. Sumpter, Yongjie Wei, Vanessa Ginet, Liying Zhang, Bruce Posner, Khoa A. Tran, Douglas R. Green, Ramnik J. Xavier, Stanley Y. Shaw, Peter G H Clarke, Julien Puyal, Beth Levine

Research output: Contribution to journalArticle

224 Citations (Scopus)

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 hypoxiä Cischemia 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.

Original languageEnglish (US)
Pages (from-to)20364-20371
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number51
DOIs
StatePublished - Dec 17 2013

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Autophagy
Starvation
Cell Death
Ischemia
Peptides
Hypoxis
Cardiac Glycosides
United States Food and Drug Administration
sodium-translocating ATPase
Hypoxia
Pharmacology
Apoptosis
Neurons
Food
In Vitro Techniques
Beclin-1

ASJC Scopus subject areas

  • General

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Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. / Liu, Yang; Shoji-Kawata, Sanae; Sumpter, Rhea M.; Wei, Yongjie; Ginet, Vanessa; Zhang, Liying; Posner, Bruce; Tran, Khoa A.; Green, Douglas R.; Xavier, Ramnik J.; Shaw, Stanley Y.; Clarke, Peter G H; Puyal, Julien; Levine, Beth.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 51, 17.12.2013, p. 20364-20371.

Research output: Contribution to journalArticle

Liu, Yang ; Shoji-Kawata, Sanae ; Sumpter, Rhea M. ; Wei, Yongjie ; Ginet, Vanessa ; Zhang, Liying ; Posner, Bruce ; Tran, Khoa A. ; Green, Douglas R. ; Xavier, Ramnik J. ; Shaw, Stanley Y. ; Clarke, Peter G H ; Puyal, Julien ; Levine, Beth. / Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 51. pp. 20364-20371.
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AU - Liu, Yang

AU - Shoji-Kawata, Sanae

AU - Sumpter, Rhea M.

AU - Wei, Yongjie

AU - Ginet, Vanessa

AU - Zhang, Liying

AU - Posner, Bruce

AU - Tran, Khoa A.

AU - Green, Douglas R.

AU - Xavier, Ramnik J.

AU - Shaw, Stanley Y.

AU - Clarke, Peter G H

AU - Puyal, Julien

AU - Levine, Beth

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AB - 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 hypoxiä Cischemia 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.

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