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Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

View ORCID ProfileEduardo U. Anaya, Akram Etemadi Amin, Michael J. Wester, Michael E. Danielson, Kyle S. Michel, View ORCID ProfileAaron K. Neumann
doi: https://doi.org/10.1101/824995
Eduardo U. Anaya
1Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, NM, USA, 87131
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Akram Etemadi Amin
1Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, NM, USA, 87131
2Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM, USA 87131
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Michael J. Wester
3Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM, USA, 87131
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Michael E. Danielson
4ImmunoResearch Inc., Eagan, MN, USA, 55121
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Kyle S. Michel
4ImmunoResearch Inc., Eagan, MN, USA, 55121
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Aaron K. Neumann
1Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, NM, USA, 87131
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  • For correspondence: akneumann@salud.unm.edu
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Abstract

Dectin-1A is a C-type Lectin innate immunoreceptor that recognizes β-(1,3;1,6)-glucan, a structural component of Candida species cell walls. The higher order structure of β-glucans ranges from random coil to insoluble fiber due to varying degrees of tertiary (helical) and quaternary structure. Model Saccharomyces cerevisiae β-glucans of medium and high molecular weight (MMW and HMW, respectively) are highly structured. In contrast, low MW glucan (LMW) is much less structured. Despite similar affinity for Dectin-1A, the ability of glucans to induce Dectin-1A mediated calcium influx and Syk phosphorylation positively correlates with their degree of higher order structure. Chemical denaturation and renaturation of MMW glucan showed that glucan structure determines agonistic potential, but not binding affinity, for Dectin-1A. We explored the role of glucan structure on Dectin-1A oligomerization, which is thought to be required for Dectin-1 signaling. Glucan signaling decreased Dectin-1A diffusion coefficient in inverse proportion to glucan structural content, which was consistent with Dectin-1A aggregation. Förster Resonance Energy Transfer (FRET) measurements revealed that molecular aggregation of Dectin-1 occurs in a manner dependent upon glucan higher order structure. Number and Brightness analysis specifically confirmed an increase in the Dectin-1A dimer and oligomer populations that is correlated with glucan structure content. Comparison of receptor modeling data with FRET measurements confirms that in resting cells, Dectin-1A is predominantly in a monomeric state. Super Resolution Microscopy revealed that glucan-stimulated Dectin-1 aggregates are very small (<15 nm) collections of a few engaged receptors. Finally, FRET measurements confirmed increased molecular aggregation of Dectin-1A at fungal particle contact sites in a manner that positively correlated with the degree of exposed glucan on the particle surface. These results indicate that Dectin-1A senses the solution conformation of β-glucans through their varying ability to drive receptor dimer/oligomer formation and activation of membrane proximal signaling events.

Competing Interest Statement

MD & KM are employees of ImmunoResearch, Inc, which provided reagents used in this study.

Copyright 
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 4.0 International license.
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Posted May 25, 2020.
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Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls
Eduardo U. Anaya, Akram Etemadi Amin, Michael J. Wester, Michael E. Danielson, Kyle S. Michel, Aaron K. Neumann
bioRxiv 824995; doi: https://doi.org/10.1101/824995
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Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls
Eduardo U. Anaya, Akram Etemadi Amin, Michael J. Wester, Michael E. Danielson, Kyle S. Michel, Aaron K. Neumann
bioRxiv 824995; doi: https://doi.org/10.1101/824995

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