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

Résultat de recherche: Articleexamen par les pairs

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'origineEnglish
Pages (de-à)160-171
Nombre de pages12
JournalCell Host and Microbe
Volume2
Numéro de publication3
DOI
Statut de publicationPublished - sept. 13 2007
Publié à l'externeOui

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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