Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation
ABSTRACT Enteropathogenic Escherichia coli and enterohemorrhagic E. coli (EPEC and EHEC, respectively) are extracellular pathogens that reorganize the host cell cytoskeleton to form “actin pedestals” beneath the tightly adherent bacteria, a critical step in pathogenesis. EPEC and EHEC inject effecto...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01876-19 |
| _version_ | 1819009902433009664 |
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| author | Vikash Singh Anthony Davidson Peter J. Hume Vassilis Koronakis |
| author_facet | Vikash Singh Anthony Davidson Peter J. Hume Vassilis Koronakis |
| author_sort | Vikash Singh |
| collection | DOAJ |
| description | ABSTRACT Enteropathogenic Escherichia coli and enterohemorrhagic E. coli (EPEC and EHEC, respectively) are extracellular pathogens that reorganize the host cell cytoskeleton to form “actin pedestals” beneath the tightly adherent bacteria, a critical step in pathogenesis. EPEC and EHEC inject effector proteins that manipulate host cell signaling cascades to trigger pedestal assembly. One such effector, EspG, has been reported to bind and activate p21-activated kinase (PAK), a key cytoskeletal regulator, but the function of this interaction and whether it impacts pedestal assembly are unknown. Here, we demonstrate that deletion of espG significantly impairs pedestal formation and attachment by both EPEC and EHEC. This role of EspG is shown to be dependent on its interaction with PAK. Unexpectedly, EspG was able to subvert PAK only in the presence of Rho family small GTPases, which function to both concentrate PAK at the membrane and stimulate PAK activation. Our findings reveal a novel mechanism by which EspG hijacks PAK and sustains its active state to drive bacterial attachment to host cells. IMPORTANCE Enteropathogenic E. coli and enterohemorrhagic E. coli (EPEC and EHEC, respectively) remain a significant global health problem. Both EPEC and EHEC initiate infection by attaching to cells in the host intestine, triggering the formation of actin-rich “pedestal” structures directly beneath the adherent pathogen. These bacteria inject their own receptor into host cells, which upon binding to a protein on the pathogen surface triggers pedestal formation. Multiple other proteins are also delivered into the cells of the host intestine, but how they contribute to disease is often less clear. Here, we show how one of these injected proteins, EspG, hijacks a host signaling pathway for pedestal production. This provides new insights into this essential early stage in EPEC and EHEC disease. |
| first_indexed | 2024-12-21T01:03:45Z |
| format | Article |
| id | doaj.art-881b0ecdafa640f1b338d8fe887cc529 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-21T01:03:45Z |
| publishDate | 2019-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-881b0ecdafa640f1b338d8fe887cc5292022-12-21T19:21:06ZengAmerican Society for MicrobiologymBio2150-75112019-08-0110410.1128/mBio.01876-19Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal FormationVikash Singh0Anthony Davidson1Peter J. Hume2Vassilis Koronakis3Department of Pathology, University of Cambridge, Cambridge, United KingdomDepartment of Pathology, University of Cambridge, Cambridge, United KingdomDepartment of Pathology, University of Cambridge, Cambridge, United KingdomDepartment of Pathology, University of Cambridge, Cambridge, United KingdomABSTRACT Enteropathogenic Escherichia coli and enterohemorrhagic E. coli (EPEC and EHEC, respectively) are extracellular pathogens that reorganize the host cell cytoskeleton to form “actin pedestals” beneath the tightly adherent bacteria, a critical step in pathogenesis. EPEC and EHEC inject effector proteins that manipulate host cell signaling cascades to trigger pedestal assembly. One such effector, EspG, has been reported to bind and activate p21-activated kinase (PAK), a key cytoskeletal regulator, but the function of this interaction and whether it impacts pedestal assembly are unknown. Here, we demonstrate that deletion of espG significantly impairs pedestal formation and attachment by both EPEC and EHEC. This role of EspG is shown to be dependent on its interaction with PAK. Unexpectedly, EspG was able to subvert PAK only in the presence of Rho family small GTPases, which function to both concentrate PAK at the membrane and stimulate PAK activation. Our findings reveal a novel mechanism by which EspG hijacks PAK and sustains its active state to drive bacterial attachment to host cells. IMPORTANCE Enteropathogenic E. coli and enterohemorrhagic E. coli (EPEC and EHEC, respectively) remain a significant global health problem. Both EPEC and EHEC initiate infection by attaching to cells in the host intestine, triggering the formation of actin-rich “pedestal” structures directly beneath the adherent pathogen. These bacteria inject their own receptor into host cells, which upon binding to a protein on the pathogen surface triggers pedestal formation. Multiple other proteins are also delivered into the cells of the host intestine, but how they contribute to disease is often less clear. Here, we show how one of these injected proteins, EspG, hijacks a host signaling pathway for pedestal production. This provides new insights into this essential early stage in EPEC and EHEC disease.https://journals.asm.org/doi/10.1128/mBio.01876-19actinEPECEspGGTPasesp21-activated kinases |
| spellingShingle | Vikash Singh Anthony Davidson Peter J. Hume Vassilis Koronakis Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation mBio actin EPEC EspG GTPases p21-activated kinases |
| title | Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation |
| title_full | Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation |
| title_fullStr | Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation |
| title_full_unstemmed | Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation |
| title_short | Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation |
| title_sort | pathogenic named content content type genus species escherichia coli named content hijacks gtpase activated p21 activated kinase for actin pedestal formation |
| topic | actin EPEC EspG GTPases p21-activated kinases |
| url | https://journals.asm.org/doi/10.1128/mBio.01876-19 |
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