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J Immunol. 2019 Jun 1;202(11):3256-3266. doi: 10.4049/jimmunol.1801384. Epub 2019 Apr 22.

Tetraspanin CD82 Organizes Dectin-1 into Signaling Domains to Mediate Cellular Responses to Candida albicans.

Author information

1
Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114.
2
Immunology Program, Benaroya Research Institute, Seattle, WA 98101.
3
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101.
4
Biomedical Engineering and Biotechnology, University of Massachusetts Medical School, Worcester, MA 01655.
5
Department of Medicine, Harvard Medical School, Boston, MA 02115.
6
Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114.
7
Department of Developmental Immunology, Massachusetts General Hospital, Boston, MA 02114.
8
Broad Institute of Harvard and MIT, Cambridge, MA 02142.
9
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114.
10
Inserm, Unité 1193, 94800 Villejuif, France.
11
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
12
Center for Systems Biology, Harvard University, Boston, MA 02115.
13
Gastrointestinal Unit/Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114; and.
14
Department of Cellular and Molecular Medicine, University of Arizona Health Sciences, Tucson, AZ 85724.
15
Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; jvyas@mgh.harvard.edu.

Abstract

Tetraspanins are a family of proteins possessing four transmembrane domains that help in lateral organization of plasma membrane proteins. These proteins interact with each other as well as other receptors and signaling proteins, resulting in functional complexes called "tetraspanin microdomains." Tetraspanins, including CD82, play an essential role in the pathogenesis of fungal infections. Dectin-1, a receptor for the fungal cell wall carbohydrate β-1,3-glucan, is vital to host defense against fungal infections. The current study identifies a novel association between tetraspanin CD82 and Dectin-1 on the plasma membrane of Candida albicans-containing phagosomes independent of phagocytic ability. Deletion of CD82 in mice resulted in diminished fungicidal activity, increased C. albicans viability within macrophages, and decreased cytokine production (TNF-α, IL-1β) at both mRNA and protein level in macrophages. Additionally, CD82 organized Dectin-1 clustering in the phagocytic cup. Deletion of CD82 modulates Dectin-1 signaling, resulting in a reduction of Src and Syk phosphorylation and reactive oxygen species production. CD82 knockout mice were more susceptible to C. albicans as compared with wild-type mice. Furthermore, patient C. albicans-induced cytokine production was influenced by two human CD82 single nucleotide polymorphisms, whereas an additional CD82 single nucleotide polymorphism increased the risk for candidemia independent of cytokine production. Together, these data demonstrate that CD82 organizes the proper assembly of Dectin-1 signaling machinery in response to C. albicans.

PMID:
31010852
PMCID:
PMC6529278
[Available on 2020-06-01]
DOI:
10.4049/jimmunol.1801384

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