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

Joel M.J. Tan; Nora Mellouk; Suzanne E. Osborne; Dustin A. Ammendolia; Diana N. Dyer; Ren Li; Diede Brunen; Jorik M. van Rijn; Ju Huang; Mark A. Czuczman; Marija A. Cemma; Amy M. Won; Christopher M. Yip; Ramnik J. Xavier; Donna A. MacDuff; Fulvio Reggiori; Jayanta Debnath; Tamotsu Yoshimori; Peter K. Kim; Gregory D. Fairn; Etienne Coyaud; Brian Raught; Aleixo M. Muise; Darren E. Higgins; John H. Brumell

doi:10.1038/s41564-018-0293-5

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

Joel M.J. Tan, Nora Mellouk, Suzanne E. Osborne, Dustin A. Ammendolia, Diana N. Dyer, Ren Li, Diede Brunen, Jorik M. van Rijn, Ju Huang, Mark A. Czuczman, Marija A. Cemma, Amy M. Won, Christopher M. Yip, Ramnik J. Xavier, Donna A. MacDuff, Fulvio Reggiori, Jayanta Debnath, Tamotsu Yoshimori, Peter K. Kim, Gregory D. FairnEtienne Coyaud, Brian Raught, Aleixo M. Muise, Darren E. Higgins, John H. Brumell

Research output: Contribution to journal › Article › peer-review

61 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1472-1485
Number of pages	14
Journal	Nature Microbiology
Volume	3
Issue number	12
DOIs	https://doi.org/10.1038/s41564-018-0293-5
Publication status	Published - Dec 1 2018
Externally published	Yes

Bibliographical note

Funding Information:
We are grateful to E.A. Creasey, A. Draeger, V. Gerke, S. Grinstein, A. Hostettles, N. Mizushima, D. Portnoy, A. Ratner, D. Rubinsztein and R. Truant for providing reagents and advice, and to the SickKids Hospital Flow and Mass Cytometry Facility for help with flow cytometry. J.H.B. holds the Pitblado Chair in Cell Biology. Infrastructure for the Brumell Laboratory was provided by a John Evans Leadership Fund grant from the Canadian Foundation for Innovation and the Ontario Innovation Trust. S.E.O. and N.M. were supported by a fellowship from the Research Training Centre at the Hospital for Sick Children. S.E.O. and J.H. were supported by CIHR fellowships. D.B. was supported by the Dutch Digestive Foundation. D.A.A. and M.A.C. were supported by a studentship from the Research Training Committee at the Hospital for Sick Children and an NSERC CGS-M scholarship. M.A.C. was supported by a University of Toronto Open Fellowship. M.C. was supported by an NSERC PGS-D scholarship and a CIHR Training Fellowship (no. TGF-53877). This work was supported by operating grants from The Arthritis Society of Canada (grant no. RG11/013) and the Canadian Institutes of Health Research (grant nos. MOP#97756, PJT#148668 and FDN154329).

Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus Subject Areas

Microbiology
Immunology
Applied Microbiology and Biotechnology
Genetics
Microbiology (medical)
Cell Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1038/s41564-018-0293-5

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Tan, J. M. J., Mellouk, N., Osborne, S. E., Ammendolia, D. A., Dyer, D. N., Li, R., Brunen, D., van Rijn, J. M., Huang, J., Czuczman, M. A., Cemma, M. A., Won, A. M., Yip, C. M., Xavier, R. J., MacDuff, D. A., Reggiori, F., Debnath, J., Yoshimori, T., Kim, P. K., ... Brumell, J. H. (2018). An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread. Nature Microbiology, 3(12), 1472-1485. https://doi.org/10.1038/s41564-018-0293-5

Tan, JMJ, Mellouk, N, Osborne, SE, Ammendolia, DA, Dyer, DN, Li, R, Brunen, D, van Rijn, JM, Huang, J, Czuczman, MA, Cemma, MA, Won, AM, Yip, CM, Xavier, RJ, MacDuff, DA, Reggiori, F, Debnath, J, Yoshimori, T, Kim, PK, Fairn, GD, Coyaud, E, Raught, B, Muise, AM, Higgins, DE & Brumell, JH 2018, 'An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread', Nature Microbiology, vol. 3, no. 12, pp. 1472-1485. https://doi.org/10.1038/s41564-018-0293-5

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title = "An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread",

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.",

author = "Tan, {Joel M.J.} and Nora Mellouk and Osborne, {Suzanne E.} and Ammendolia, {Dustin A.} and Dyer, {Diana N.} and Ren Li and Diede Brunen and {van Rijn}, {Jorik M.} and Ju Huang and Czuczman, {Mark A.} and Cemma, {Marija A.} and Won, {Amy M.} and Yip, {Christopher M.} and Xavier, {Ramnik J.} and MacDuff, {Donna A.} and Fulvio Reggiori and Jayanta Debnath and Tamotsu Yoshimori and Kim, {Peter K.} and Fairn, {Gregory D.} and Etienne Coyaud and Brian Raught and Muise, {Aleixo M.} and Higgins, {Darren E.} and Brumell, {John H.}",

note = "Funding Information: We are grateful to E.A. Creasey, A. Draeger, V. Gerke, S. Grinstein, A. Hostettles, N. Mizushima, D. Portnoy, A. Ratner, D. Rubinsztein and R. Truant for providing reagents and advice, and to the SickKids Hospital Flow and Mass Cytometry Facility for help with flow cytometry. J.H.B. holds the Pitblado Chair in Cell Biology. Infrastructure for the Brumell Laboratory was provided by a John Evans Leadership Fund grant from the Canadian Foundation for Innovation and the Ontario Innovation Trust. S.E.O. and N.M. were supported by a fellowship from the Research Training Centre at the Hospital for Sick Children. S.E.O. and J.H. were supported by CIHR fellowships. D.B. was supported by the Dutch Digestive Foundation. D.A.A. and M.A.C. were supported by a studentship from the Research Training Committee at the Hospital for Sick Children and an NSERC CGS-M scholarship. M.A.C. was supported by a University of Toronto Open Fellowship. M.C. was supported by an NSERC PGS-D scholarship and a CIHR Training Fellowship (no. TGF-53877). This work was supported by operating grants from The Arthritis Society of Canada (grant no. RG11/013) and the Canadian Institutes of Health Research (grant nos. MOP#97756, PJT#148668 and FDN154329). Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41564-018-0293-5",

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AU - Tan, Joel M.J.

AU - Mellouk, Nora

AU - Osborne, Suzanne E.

AU - Ammendolia, Dustin A.

AU - Dyer, Diana N.

AU - Li, Ren

AU - Brunen, Diede

AU - van Rijn, Jorik M.

AU - Huang, Ju

AU - Czuczman, Mark A.

AU - Cemma, Marija A.

AU - Won, Amy M.

AU - Yip, Christopher M.

AU - Xavier, Ramnik J.

AU - MacDuff, Donna A.

AU - Reggiori, Fulvio

AU - Debnath, Jayanta

AU - Yoshimori, Tamotsu

AU - Kim, Peter K.

AU - Fairn, Gregory D.

AU - Coyaud, Etienne

AU - Raught, Brian

AU - Muise, Aleixo M.

AU - Higgins, Darren E.

AU - Brumell, John H.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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PubMed: MeSH publication types

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