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Receptor-kinase EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article number102419
JournalJournal of Biological Chemistry
Volume298
Issue number10
DOIs
PublishedOct 2022

Bibliographical note

Funding Information: We thank Bernhard Hube for providing fungal strains and members of the Centre for Host-Microbiome Interactions at King's College London and members of the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh for helpful suggestions. D. L. M, J. H. S. L. G. and J. R. N. conceptualization; N. O. P. methodology; N. O. P. L. L. A. T. O. W. H. and D. N. W. investigation; N. O. P. writing–original draft; S. L. G. J. P. R. and J. N. writing–review & editing; J. P. R. D. L. M. and J. R. N. supervision; J. R. N. project administration; S. L. G. D. L. M. and J. R. N. funding acquisition. S. L. G was supported by the National Institutes of Health (NIH, DE022550). J. R. N. was supported by the Wellcome Trust (214229_Z_18_Z), the NIH (DE022550), and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility (IS-BRC-1215-20006). D. L. M was supported by the UKRI-BBSRC (BB/S016899/1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: S. L. G was supported by the National Institutes of Health (NIH, DE022550). J. R. N. was supported by the Wellcome Trust (214229_Z_18_Z), the NIH (DE022550), and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility ( IS-BRC-1215-20006 ). D. L. M was supported by the UKRI-BBSRC (BB/S016899/1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2022 The Authors

King's Authors

Abstract

Candida albicans (C. albicans) is a dimorphic commensal human fungal pathogen that can cause severe oropharyngeal candidiasis (oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for C. albicans pathogenesis at mucosal surfaces. Candidalysin is produced in the hyphal invasion pocket and triggers cell damage responses in OECs. Candidalysin also activates multiple MAPK-based signaling events that collectively drive the production of downstream inflammatory mediators that coordinate downstream innate and adaptive immune responses. The activities of candidalysin are dependent on signaling through the epidermal growth factor receptor (EGFR). Here, we interrogated known EGFR-MAPK signaling intermediates for their roles mediating the OEC response to C. albicans infection. Using RNA silencing and pharmacological inhibition, we identified five key adaptors, including growth factor receptor-bound protein 2 (Grb2), Grb2-associated binding protein 1 (Gab1), Src homology and collagen (Shc), SH2-containing protein tyrosine phosphatase-2 (Shp2), and casitas B-lineage lymphoma (c-Cbl). We determined that all of these signaling effectors were inducibly phosphorylated in response to C. albicans. These phosphorylation events occurred in a candidalysin-dependent manner and additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs), and cellular calcium flux to activate a complete OEC response to fungal infection. Of these, Gab1, Grb2, and Shp2 were the dominant drivers of ERK1/2 activation and the subsequent production of downstream innate-acting cytokines. Together, these results identify the key adaptor proteins that drive the EGFR signaling mechanisms that underlie oral epithelial responses to C. albicans.

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