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The Globular C1q Receptor Is Required for Epidermal Growth Factor Receptor Signaling during Candida albicans Infection

Phan, Quynh T. and Lin, Jianfeng and Solis, Norma V. and Eng, Michael and Swidergall, Marc and Wang, Feng and Li, Shan and Gaffen, Sarah L. and Chou, Tsui-Fen and Filler, Scott G. (2021) The Globular C1q Receptor Is Required for Epidermal Growth Factor Receptor Signaling during Candida albicans Infection. mBio, 12 (6). Art. No. e02716-21. ISSN 2150-7511. doi:10.1128/mBio.02716-21. https://resolver.caltech.edu/CaltechAUTHORS:20210528-084342141

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Abstract

During oropharyngeal candidiasis, Candida albicans activates the epidermal growth factor receptor (EGFR), which induces oral epithelial cells to endocytose the fungus and synthesize proinflammatory mediators. To elucidate EGFR signaling pathways that are stimulated by C. albicans, we used proteomics to identify 1,214 proteins that were associated with EGFR in C. albicans-infected cells. Seven of these proteins were selected for additional study. Among these proteins, WW domain-binding protein 2, Toll-interacting protein, interferon-induced transmembrane protein 3 (IFITM3), and the globular C1q receptor (gC1qR) were found to associate with EGFR in viable oral epithelial cells. Each of these proteins was required for maximal endocytosis of C. albicans, and all regulated fungus-induced production of interleukin-1β (IL-1β) and/or IL-8, either positively or negatively. gC1qR was found to function as a key coreceptor with EGFR. Interacting with the C. albicans Als3 invasin, gC1qR was required for the fungus to induce autophosphorylation of both EGFR and the ephrin type A receptor 2. The combination of gC1qR and EGFR was necessary for maximal endocytosis of C. albicans and secretion of IL-1β, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by human oral epithelial cells. In mouse oral epithelial cells, inhibition of gC1qR failed to block C. albicans-induced phosphorylation, and knockdown of IFITM3 did not inhibit C. albicans endocytosis, indicating that gC1qR and IFITM3 function differently in mouse versus human oral epithelial cells. Thus, this work provides an atlas of proteins that associate with EGFR and identifies several that play a central role in the response of human oral epithelial cells to C. albicans infection.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1128/mBio.02716-21DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8561387/PubMed CentralArticle
https://doi.org/10.1101/2021.05.25.445718DOIDiscussion Paper
ORCID:
AuthorORCID
Lin, Jianfeng0000-0002-5202-6304
Swidergall, Marc0000-0002-5261-6267
Gaffen, Sarah L.0000-0001-8511-2041
Chou, Tsui-Fen0000-0003-2410-2186
Filler, Scott G.0000-0001-7278-3700
Additional Information:© 2021 Phan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Received 11 September 2021; Accepted 21 September 2021; Published 2 November 2021. We thank Adam Diab for assistance with tissue culture. The work was supported in part by NIH grants R01DE026600 and R01AI124566 to S.G.F., R00DE026856 to M.S., and DE022550 to S.L.G.
Funders:
Funding AgencyGrant Number
NIHR01DE026600
NIHR01AI124566
NIHR00DE026856
NIHDE022550
Subject Keywords:Candida albicans, oral epithelial cells, endocytosis, epidermal growth factor receptor, host defense
Issue or Number:6
DOI:10.1128/mBio.02716-21
Record Number:CaltechAUTHORS:20210528-084342141
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210528-084342141
Official Citation:Phan QT, Lin J, Solis NV, Eng M, Swidergall M, Wang F, Li S, Gaffen SL, Chou T-F, Filler SG. 2021. The globular C1q receptor is required for epidermal growth factor receptor signaling during Candida albicans infection. mBio 12:e02716-21. https://doi.org/10.1128/mBio.02716-21
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109293
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 May 2021 15:58
Last Modified:03 Feb 2022 19:11

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