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Nat Microbiol. 2018 Dec;3(12):1472-1485. doi: 10.1038/s41564-018-0293-5. Epub 2018 Nov 26.

An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread.

Author information

1
Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
2
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
3
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
4
Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Utrecht, the Netherlands.
5
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
6
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
7
Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
8
Department of Cell Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
9
Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
10
Department of Cellular Regulation and Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
11
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
12
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
13
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
14
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
15
Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
16
SickKids IBD Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
17
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
18
Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada. john.brumell@sickkids.ca.
19
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. john.brumell@sickkids.ca.
20
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. john.brumell@sickkids.ca.
21
SickKids IBD Centre, Hospital for Sick Children, Toronto, Ontario, Canada. john.brumell@sickkids.ca.

Abstract

Plasma membrane integrity is essential for the viability of eukaryotic cells. In response to bacterial pore-forming toxins, disrupted regions of the membrane are rapidly repaired. However, the pathways that mediate plasma membrane repair are unclear. Here we show that autophagy-related (ATG) protein ATG16L1 and its binding partners ATG5 and ATG12 are required for plasma membrane repair through a pathway independent of macroautophagy. ATG16L1 is required for lysosome fusion with the plasma membrane and blebbing responses that promote membrane repair. ATG16L1 deficiency causes accumulation of cholesterol in lysosomes that contributes to defective membrane repair. Cell-to-cell spread by Listeria monocytogenes requires membrane damage by the bacterial toxin listeriolysin O, which is restricted by ATG16L1-dependent membrane repair. Cells harbouring the ATG16L1 T300A allele associated with inflammatory bowel disease were also found to accumulate cholesterol and be defective in repair, linking a common inflammatory disease to plasma membrane integrity. Thus, plasma membrane repair could be an important therapeutic target for the treatment of bacterial infections and inflammatory disorders.

Comment in

PMID:
30478389
DOI:
10.1038/s41564-018-0293-5
[Indexed for MEDLINE]

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