The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function

Jinoh Kim; Ajitha Thanabalasuriar; Tessa Chaworth-Musters; J. Chris Fromme; Elizabeth A. Frey; Paula I I. Lario; Pavel Metalnikov; Keyrillos Rizg; Nikhil A. Thomas; Sau Fung Lee; Elizabeth L. Hartland; Philip R R. Hardwidge; Tony Pawson; Natalie C. Strynadka; B. Brett Finlay; Randy Schekman; Samantha Gruenheid

doi:10.1016/j.chom.2007.07.010

The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function

Jinoh Kim, Ajitha Thanabalasuriar, Tessa Chaworth-Musters, J. Chris Fromme, Elizabeth A. Frey, Paula I I. Lario, Pavel Metalnikov, Keyrillos Rizg, Nikhil A. Thomas, Sau Fung Lee, Elizabeth L. Hartland, Philip R R. Hardwidge, Tony Pawson, Natalie C. Strynadka, B. Brett Finlay, Randy Schekman, Samantha Gruenheid

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91 Citations (Scopus)

Résumé

Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) maintain an extracellular lifestyle and use a type III secretion system to translocate effector proteins into the host cytosol. These effectors manipulate host pathways to favor bacterial replication and survival. NleA is an EHEC/EPEC- and related species-specific translocated effector protein that is essential for bacterial virulence. However, the mechanism by which NleA impacts virulence remains undetermined. Here we demonstrate that NleA compromises the Sec23/24 complex, a component of the mammalian COPII protein coat that shapes intracellular protein transport vesicles, by directly binding Sec24. Expression of an NleA-GFP fusion protein reduces the efficiency of cellular secretion by 50%, and secretion is inhibited in EPEC-infected cells. Direct biochemical experiments show that NleA inhibits COPII-dependent protein export from the endoplasmic reticulum. Collectively, these findings indicate that disruption of COPII function in host cells contributes to the virulence of EPEC and EHEC.

Langue d'origine	English
Pages (de-à)	160-171
Nombre de pages	12
Journal	Cell Host and Microbe
Volume	2
Numéro de publication	3
DOI	https://doi.org/10.1016/j.chom.2007.07.010
Statut de publication	Published - sept. 13 2007
Publié à l'externe	Oui

Note bibliographique

Funding Information:
The authors wish to thank Jon Kagan for helpful discussions, Craig Roy for providing the SEAP plasmid, Jennifer Lippincott-Schwartz for providing the VSV-G plasmid, Matlashewski Lab for the use of the Tube Luminometer, Archana Srivastava and John Presley for advice regarding the VSV-G experiment, and Lei Zhu for technical assistance with animal experiments. S.G. is a Canada Research Chair in Bacterial Pathogenesis; R.S. is an Investigator of the HHMI; B.B.F. is a HHMI International Research Scholar, a CIHR Distinguished Investigator, and the UBC Peter Wall Distinguished Professor; N.C.S. is a HHMI International Scholar, CIHR Investigator, and MSFHR Senior Scholar; T.P. is a CIHR distinguished investigator; and P.I.L. is a CIHR fellow. E.L.H. is supported by grants from the ARC and NHMRC. S.F.L. is the recipient of a Monash Graduate Scholarship and a Monash International Postgraduate Research Scholarship. This project was supported through funding from CIHR operating grants to S.G., T.P., and B.B.F.; a Miller Foundation fellowship to J.C.F.; a Genome Canada Grant to T.P.; and support from the HHMI for N.C.S., B.B.F., and R.S.

ASJC Scopus Subject Areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2007.07.010

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Kim, J., Thanabalasuriar, A., Chaworth-Musters, T., Fromme, J. C., Frey, E. A., Lario, PI. I., Metalnikov, P., Rizg, K., Thomas, N. A., Lee, S. F., Hartland, E. L., Hardwidge, PR. R., Pawson, T., Strynadka, N. C., Finlay, B. B., Schekman, R., & Gruenheid, S. (2007). The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function. Cell Host and Microbe, 2(3), 160-171. https://doi.org/10.1016/j.chom.2007.07.010

Kim, J, Thanabalasuriar, A, Chaworth-Musters, T, Fromme, JC, Frey, EA, Lario, PII, Metalnikov, P, Rizg, K, Thomas, NA, Lee, SF, Hartland, EL, Hardwidge, PRR, Pawson, T, Strynadka, NC, Finlay, BB, Schekman, R & Gruenheid, S 2007, 'The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function', Cell Host and Microbe, vol. 2, n° 3, pp. 160-171. https://doi.org/10.1016/j.chom.2007.07.010

@article{b2373d2cb5cc4593b281b9140edac1c0,

title = "The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function",

abstract = "Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) maintain an extracellular lifestyle and use a type III secretion system to translocate effector proteins into the host cytosol. These effectors manipulate host pathways to favor bacterial replication and survival. NleA is an EHEC/EPEC- and related species-specific translocated effector protein that is essential for bacterial virulence. However, the mechanism by which NleA impacts virulence remains undetermined. Here we demonstrate that NleA compromises the Sec23/24 complex, a component of the mammalian COPII protein coat that shapes intracellular protein transport vesicles, by directly binding Sec24. Expression of an NleA-GFP fusion protein reduces the efficiency of cellular secretion by 50%, and secretion is inhibited in EPEC-infected cells. Direct biochemical experiments show that NleA inhibits COPII-dependent protein export from the endoplasmic reticulum. Collectively, these findings indicate that disruption of COPII function in host cells contributes to the virulence of EPEC and EHEC.",

author = "Jinoh Kim and Ajitha Thanabalasuriar and Tessa Chaworth-Musters and Fromme, {J. Chris} and Frey, {Elizabeth A.} and Lario, {Paula I I.} and Pavel Metalnikov and Keyrillos Rizg and Thomas, {Nikhil A.} and Lee, {Sau Fung} and Hartland, {Elizabeth L.} and Hardwidge, {Philip R R.} and Tony Pawson and Strynadka, {Natalie C.} and Finlay, {B. Brett} and Randy Schekman and Samantha Gruenheid",

note = "Funding Information: The authors wish to thank Jon Kagan for helpful discussions, Craig Roy for providing the SEAP plasmid, Jennifer Lippincott-Schwartz for providing the VSV-G plasmid, Matlashewski Lab for the use of the Tube Luminometer, Archana Srivastava and John Presley for advice regarding the VSV-G experiment, and Lei Zhu for technical assistance with animal experiments. S.G. is a Canada Research Chair in Bacterial Pathogenesis; R.S. is an Investigator of the HHMI; B.B.F. is a HHMI International Research Scholar, a CIHR Distinguished Investigator, and the UBC Peter Wall Distinguished Professor; N.C.S. is a HHMI International Scholar, CIHR Investigator, and MSFHR Senior Scholar; T.P. is a CIHR distinguished investigator; and P.I.L. is a CIHR fellow. E.L.H. is supported by grants from the ARC and NHMRC. S.F.L. is the recipient of a Monash Graduate Scholarship and a Monash International Postgraduate Research Scholarship. This project was supported through funding from CIHR operating grants to S.G., T.P., and B.B.F.; a Miller Foundation fellowship to J.C.F.; a Genome Canada Grant to T.P.; and support from the HHMI for N.C.S., B.B.F., and R.S. ",

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doi = "10.1016/j.chom.2007.07.010",

language = "English",

volume = "2",

pages = "160--171",

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T1 - The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function

AU - Kim, Jinoh

AU - Thanabalasuriar, Ajitha

AU - Chaworth-Musters, Tessa

AU - Fromme, J. Chris

AU - Frey, Elizabeth A.

AU - Lario, Paula I I.

AU - Metalnikov, Pavel

AU - Rizg, Keyrillos

AU - Thomas, Nikhil A.

AU - Lee, Sau Fung

AU - Hartland, Elizabeth L.

AU - Hardwidge, Philip R R.

AU - Pawson, Tony

AU - Strynadka, Natalie C.

AU - Finlay, B. Brett

AU - Schekman, Randy

AU - Gruenheid, Samantha

N1 - Funding Information: The authors wish to thank Jon Kagan for helpful discussions, Craig Roy for providing the SEAP plasmid, Jennifer Lippincott-Schwartz for providing the VSV-G plasmid, Matlashewski Lab for the use of the Tube Luminometer, Archana Srivastava and John Presley for advice regarding the VSV-G experiment, and Lei Zhu for technical assistance with animal experiments. S.G. is a Canada Research Chair in Bacterial Pathogenesis; R.S. is an Investigator of the HHMI; B.B.F. is a HHMI International Research Scholar, a CIHR Distinguished Investigator, and the UBC Peter Wall Distinguished Professor; N.C.S. is a HHMI International Scholar, CIHR Investigator, and MSFHR Senior Scholar; T.P. is a CIHR distinguished investigator; and P.I.L. is a CIHR fellow. E.L.H. is supported by grants from the ARC and NHMRC. S.F.L. is the recipient of a Monash Graduate Scholarship and a Monash International Postgraduate Research Scholarship. This project was supported through funding from CIHR operating grants to S.G., T.P., and B.B.F.; a Miller Foundation fellowship to J.C.F.; a Genome Canada Grant to T.P.; and support from the HHMI for N.C.S., B.B.F., and R.S.

PY - 2007/9/13

Y1 - 2007/9/13

N2 - Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) maintain an extracellular lifestyle and use a type III secretion system to translocate effector proteins into the host cytosol. These effectors manipulate host pathways to favor bacterial replication and survival. NleA is an EHEC/EPEC- and related species-specific translocated effector protein that is essential for bacterial virulence. However, the mechanism by which NleA impacts virulence remains undetermined. Here we demonstrate that NleA compromises the Sec23/24 complex, a component of the mammalian COPII protein coat that shapes intracellular protein transport vesicles, by directly binding Sec24. Expression of an NleA-GFP fusion protein reduces the efficiency of cellular secretion by 50%, and secretion is inhibited in EPEC-infected cells. Direct biochemical experiments show that NleA inhibits COPII-dependent protein export from the endoplasmic reticulum. Collectively, these findings indicate that disruption of COPII function in host cells contributes to the virulence of EPEC and EHEC.

AB - Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) maintain an extracellular lifestyle and use a type III secretion system to translocate effector proteins into the host cytosol. These effectors manipulate host pathways to favor bacterial replication and survival. NleA is an EHEC/EPEC- and related species-specific translocated effector protein that is essential for bacterial virulence. However, the mechanism by which NleA impacts virulence remains undetermined. Here we demonstrate that NleA compromises the Sec23/24 complex, a component of the mammalian COPII protein coat that shapes intracellular protein transport vesicles, by directly binding Sec24. Expression of an NleA-GFP fusion protein reduces the efficiency of cellular secretion by 50%, and secretion is inhibited in EPEC-infected cells. Direct biochemical experiments show that NleA inhibits COPII-dependent protein export from the endoplasmic reticulum. Collectively, these findings indicate that disruption of COPII function in host cells contributes to the virulence of EPEC and EHEC.

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The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function

Résumé

Note bibliographique

ASJC Scopus Subject Areas

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