Cysteine-Dependent Conformational Heterogeneity of Shigella flexneri Autotransporter IcsA and Implications of Its Function
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Description
Shigella IcsA is a versatile surface virulence factor required for early and late pathogenesis stages extracellularly and intracellularly. Despite IcsA serving as a model Type V secretion system (T5SS) autotransporter to study host-pathogen interactions, its detailed molecular architecture is poorly understood. Recently, IcsA was found to switch to a different conformation for its adhesin activity upon sensing the host stimuli by Shigella Type III secretion system (T3SS). Here, we reported that the single cysteine residue (C130) near the N terminus of the IcsA passenger had a role in IcsA adhesin activity. We also showed that the IcsA passenger (IcsAp) existed in multiple conformations, and the conformation populations were influenced by a central pair of cysteine residues (C375 and C379), which was not previously reported for any Type V autotransporter passengers. Disruption of either or both central cysteine residues altered the exposure of IcsA epitopes to polyclonal anti-IcsA antibodies previously shown to block Shigella adherence, yet without loss of IcsA intracellular functions in actin-based motility (ABM). Anti-IcsA antibody reactivity was restored when the IcsA-paired cysteine substitution mutants were expressed in an DipaD background with a constitutively active T3SS, highlighting an interplay between T3SS and T5SS. The work here uncovered a novel molecular switch empowered by a centrally localized, short-spaced cysteine pair in the Type V autotransporter IcsA that ensured conformational heterogeneity to aid IcsA evasion of host immunity.
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ID Code: | 239027 | ||||
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Item Type: | Contribution to Journal (Journal Article) | ||||
Refereed: | Yes | ||||
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Additional Information: | Funding Information: This study was supported by grants by the Australian National Health and Medical Research Council (NHMRC GNT1144046), the Clive and Vera Ramaciotti Foundations (2017HIG0119), and a Georgina Sweet Award for Women in Quantitative Biomedical Science to M.T. J.Q. received a Faculty of Science Postgraduate Scholarship from the University of Adelaide. This work made use of a microscopy facility supported by the Ian Porter Foundation. No funder had a role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. | ||||
Measurements or Duration: | 16 pages | ||||
Keywords: | adhesin, conformation heterogeneity, IcsA, Shigella flexneri | ||||
DOI: | 10.1128/spectrum.03410-22 | ||||
ISSN: | 2165-0497 | ||||
Pure ID: | 128865519 | ||||
Divisions: | Current > Research Centres > Centre for Immunology and Infection Control Current > QUT Faculties and Divisions > Faculty of Health Current > Schools > School of Biomedical Sciences |
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Funding Information: | This study was supported by grants by the Australian National Health and Medical Research Council (NHMRC GNT1144046), the Clive and Vera Ramaciotti Foundations (2017HIG0119), and a Georgina Sweet Award for Women in Quantitative Biomedical Science to M.T. J.Q. received a Faculty of Science Postgraduate Scholarship from the University of Adelaide. This work made use of a microscopy facility supported by the Ian Porter Foundation. No funder had a role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. | ||||
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Copyright Owner: | 2022 The Authors | ||||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||||
Deposited On: | 05 Apr 2023 23:55 | ||||
Last Modified: | 29 Feb 2024 13:22 |
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