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Tandem tyrosine residues in the EPEC multicargo chaperone CesT support differential type III effector translocation and early host colonization

Cameron Runte, Umang Jain, View ORCID ProfileLandon Getz, Sabrina Secord, View ORCID ProfileAsaomi Kuwae, Akio Abe, View ORCID ProfileJason LeBlanc, Andrew W Stadnyk, James B Kaper, Anne-Marie Hansen, View ORCID ProfileNikhil A Thomas
doi: https://doi.org/10.1101/270066
Cameron Runte
Dalhousie University;
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Umang Jain
Dalhousie University;
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Landon Getz
Dalhousie University;
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Sabrina Secord
Dalhousie University;
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Asaomi Kuwae
Kitasato University;
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Akio Abe
Kitasato University;
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Jason LeBlanc
Dalhousie University;
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Andrew W Stadnyk
Dalhousie University;
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James B Kaper
University of Maryland Medical School
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Anne-Marie Hansen
University of Maryland Medical School
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Nikhil A Thomas
Dalhousie University;
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  • ORCID record for Nikhil A Thomas
  • For correspondence: n.thomas@dal.ca
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Abstract

Enteropathogenic Escherichia coli (EPEC) are worldwide human enteric pathogens inflicting significant morbidity and causing large economic losses. A type 3 secretion system (T3SS) is critical for EPEC intestinal colonization, and injection of effectors into host cells contributes to cellular subversion and innate immune evasion. Here, we demonstrate that two strictly conserved C-terminal tyrosine residues, Y152 and Y153, within the multicargo T3SS chaperone CesT serve differential roles in regulating effector secretion in EPEC. Conservative substitution of both tyrosine residues to phenylalanine attenuated EPEC type 3 effector injection into host cells, and significantly limited Tir effector mediated intimate adherence, a key feature of attaching and effacing pathogenesis. Whereas CesT Y153 supported normal levels of Tir translocation, CesT Y152 was strictly required for the effector NleA to be expressed and subsequently translocated into host cells during infection. Other effectors were observed to be dependent on CesT Y152 for maximal translocation efficiency. Unexpectedly, EPEC expressing a CesT Y152, Y153F variant exhibited significantly enhanced effector translocation of many CesT-interacting effectors, further implicating Y152 in CesT functionality. A mouse infection model of EPEC intestinal disease using Citrobacter rodentium revealed that CesT tyrosine substitution variants displayed delayed colonization and were more rapidly cleared from the intestine. These data demonstrate genetically separable functions for strictly conserved tandem tyrosine residues within CesT. Tyrosine 152 of CesT is implicated in NleA expression, providing functional relevance for localized amino acid conservation. Therefore, CesT via its novel C-terminal domain, has relevant roles beyond typical T3SC that interact and stabilize effector proteins.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 22, 2018.
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Tandem tyrosine residues in the EPEC multicargo chaperone CesT support differential type III effector translocation and early host colonization
Cameron Runte, Umang Jain, Landon Getz, Sabrina Secord, Asaomi Kuwae, Akio Abe, Jason LeBlanc, Andrew W Stadnyk, James B Kaper, Anne-Marie Hansen, Nikhil A Thomas
bioRxiv 270066; doi: https://doi.org/10.1101/270066
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Tandem tyrosine residues in the EPEC multicargo chaperone CesT support differential type III effector translocation and early host colonization
Cameron Runte, Umang Jain, Landon Getz, Sabrina Secord, Asaomi Kuwae, Akio Abe, Jason LeBlanc, Andrew W Stadnyk, James B Kaper, Anne-Marie Hansen, Nikhil A Thomas
bioRxiv 270066; doi: https://doi.org/10.1101/270066

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