Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes

Oliver Florey, Sung Eun Kim, Cynthia P. Sandoval, Cole M. Haynes, Michael Overholtzer

Research output: Contribution to journalArticlepeer-review

348 Citations (Scopus)

Abstract

Autophagy normally involves the formation of double-membrane autophagosomes that mediate bulk cytoplasmic and organelle degradation. Here we report the modification of single-membrane vacuoles in cells by autophagy proteins. LC3 (Light chain 3) a component of autophagosomes, is recruited to single-membrane entotic vacuoles, macropinosomes and phagosomes harbouring apoptotic cells, in a manner dependent on the lipidation machinery including ATG5 and ATG7, and the class III phosphatidylinositol-3-kinase VPS34. These downstream components of the autophagy machinery, but not the upstream mammalian Tor (mTor)-regulated ULK-ATG13-FIP200 complex, facilitate lysosome fusion to single membranes and the degradation of internalized cargo. For entosis, a live-cell-engulfment program, the autophagy-protein-dependent fusion of lysosomes to vacuolar membranes leads to the death of internalized cells. As pathogen-containing phagosomes can be targeted in a similar manner, the death of epithelial cells by this mechanism mimics pathogen destruction. These data demonstrate that proteins of the autophagy pathway can target single-membrane vacuoles in cells in the absence of pathogenic organisms.

Original languageEnglish
Pages (from-to)1335-1343
Number of pages9
JournalNature Cell Biology
Volume13
Issue number11
DOIs
Publication statusPublished - 2011 Nov
Externally publishedYes

Bibliographical note

Funding Information:
We thank J. Durgan, I. Ganley, X. Jiang, G. Mouneimne, E. Yao, A. Spencer and members of the Overholtzer laboratory for helpful discussions, reagents and for reading the manuscript. We also thank N. Lampen of the Memorial Sloan Kettering Cancer Center Electron Microscopy Facility for processing of electron microscopy samples. This work was financially supported by a grant from the National Cancer Institute (CA154649; M.O.), The Geoffrey Beene Cancer Research Center at MSKCC (M.O.), the Louis V. Gerstner, Jr. Young Investigators Fund (M.O. and C.M.H.) and the Alfred W. Bressler Scholar Fund (C.M.H.).

ASJC Scopus subject areas

  • Cell Biology

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