The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65.
Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the type III effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ from Shigella, blocked translocation of the p65 subunit of the transcription factor, NF-ka...
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2010
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oai:doaj.org-article:db95da39b4bb43fb9bafe6e7de4ba46d2021-12-02T20:00:40ZThe type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65.1553-73661553-737410.1371/journal.ppat.1000898https://doaj.org/article/db95da39b4bb43fb9bafe6e7de4ba46d2010-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20485572/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the type III effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ from Shigella, blocked translocation of the p65 subunit of the transcription factor, NF-kappaB, to the host cell nucleus. NF-kappaB inhibition by NleE was associated with decreased IL-8 expression in EPEC-infected intestinal epithelial cells. Ectopically expressed NleE also blocked nuclear translocation of p65 and c-Rel, but not p50 or STAT1/2. NleE homologues from other attaching and effacing pathogens as well OspZ from Shigella flexneri 6 and Shigella boydii, also inhibited NF-kappaB activation and p65 nuclear import; however, a truncated form of OspZ from S. flexneri 2a that carries a 36 amino acid deletion at the C-terminus had no inhibitory activity. We determined that the C-termini of NleE and full length OspZ were functionally interchangeable and identified a six amino acid motif, IDSY(M/I)K, that was important for both NleE- and OspZ-mediated inhibition of NF-kappaB activity. We also established that NleB, encoded directly upstream from NleE, suppressed NF-kappaB activation. Whereas NleE inhibited both TNFalpha and IL-1beta stimulated p65 nuclear translocation and IkappaB degradation, NleB inhibited the TNFalpha pathway only. Neither NleE nor NleB inhibited AP-1 activation, suggesting that the modulatory activity of the effectors was specific for NF-kappaB signaling. Overall our data show that EPEC and Shigella have evolved similar T3SS-dependent means to manipulate host inflammatory pathways by interfering with the activation of selected host transcriptional regulators.Hayley J NewtonJaclyn S PearsonLuminita BadeaMichelle KellyMark LucasGavan HollowayKylie M WagstaffMichelle A DunstoneJoan SloanJames C WhisstockJames B KaperRoy M Robins-BrowneDavid A JansGad FrankelAlan D PhillipsBarbara S CoulsonElizabeth L HartlandPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 5, p e1000898 (2010) |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Hayley J Newton Jaclyn S Pearson Luminita Badea Michelle Kelly Mark Lucas Gavan Holloway Kylie M Wagstaff Michelle A Dunstone Joan Sloan James C Whisstock James B Kaper Roy M Robins-Browne David A Jans Gad Frankel Alan D Phillips Barbara S Coulson Elizabeth L Hartland The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. |
| description |
Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the type III effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ from Shigella, blocked translocation of the p65 subunit of the transcription factor, NF-kappaB, to the host cell nucleus. NF-kappaB inhibition by NleE was associated with decreased IL-8 expression in EPEC-infected intestinal epithelial cells. Ectopically expressed NleE also blocked nuclear translocation of p65 and c-Rel, but not p50 or STAT1/2. NleE homologues from other attaching and effacing pathogens as well OspZ from Shigella flexneri 6 and Shigella boydii, also inhibited NF-kappaB activation and p65 nuclear import; however, a truncated form of OspZ from S. flexneri 2a that carries a 36 amino acid deletion at the C-terminus had no inhibitory activity. We determined that the C-termini of NleE and full length OspZ were functionally interchangeable and identified a six amino acid motif, IDSY(M/I)K, that was important for both NleE- and OspZ-mediated inhibition of NF-kappaB activity. We also established that NleB, encoded directly upstream from NleE, suppressed NF-kappaB activation. Whereas NleE inhibited both TNFalpha and IL-1beta stimulated p65 nuclear translocation and IkappaB degradation, NleB inhibited the TNFalpha pathway only. Neither NleE nor NleB inhibited AP-1 activation, suggesting that the modulatory activity of the effectors was specific for NF-kappaB signaling. Overall our data show that EPEC and Shigella have evolved similar T3SS-dependent means to manipulate host inflammatory pathways by interfering with the activation of selected host transcriptional regulators. |
| format |
article |
| author |
Hayley J Newton Jaclyn S Pearson Luminita Badea Michelle Kelly Mark Lucas Gavan Holloway Kylie M Wagstaff Michelle A Dunstone Joan Sloan James C Whisstock James B Kaper Roy M Robins-Browne David A Jans Gad Frankel Alan D Phillips Barbara S Coulson Elizabeth L Hartland |
| author_facet |
Hayley J Newton Jaclyn S Pearson Luminita Badea Michelle Kelly Mark Lucas Gavan Holloway Kylie M Wagstaff Michelle A Dunstone Joan Sloan James C Whisstock James B Kaper Roy M Robins-Browne David A Jans Gad Frankel Alan D Phillips Barbara S Coulson Elizabeth L Hartland |
| author_sort |
Hayley J Newton |
| title |
The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. |
| title_short |
The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. |
| title_full |
The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. |
| title_fullStr |
The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. |
| title_full_unstemmed |
The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. |
| title_sort |
type iii effectors nlee and nleb from enteropathogenic e. coli and ospz from shigella block nuclear translocation of nf-kappab p65. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/db95da39b4bb43fb9bafe6e7de4ba46d |
| work_keys_str_mv |
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