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

• Published in: The Journal of immunology (1950) Vol. 202; no. 11; pp. 3256 - 3266
• Main Authors: Tam, Jenny M, Reedy, Jennifer L, Lukason, Daniel P, Kuna, Sunnie G, Acharya, Mridu, Khan, Nida S, Negoro, Paige E, Xu, Shuying, Ward, Rebecca A, Feldman, Michael B, Dutko, Richard A, Jeffery, Jane B, Sokolovska, Anna, Wivagg, Carl N, Lassen, Kara G, Le Naour, François, Matzaraki, Vasiliki, Garner, Ethan C, Xavier, Ramnik J, Kumar, Vinod, van de Veerdonk, Frank L, Netea, Mihai G, Miranti, Cindy K, Mansour, Michael K, Vyas, Jatin M
• Format: Journal Article
• Language: English
• Published: United States 01.06.2019
• Subjects: Animals; Candida albicans - physiology; Candidiasis - immunology; Candidiasis - metabolism; Cell Line; Cell Membrane - metabolism; Genetic Predisposition to Disease; Humans; Immunity, Cellular; Interleukin-1beta - metabolism; Kangai-1 Protein - genetics; Kangai-1 Protein - metabolism; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Macrophages - immunology; Membrane Microdomains - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Phagosomes - metabolism; Polymorphism, Single Nucleotide; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1801384

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 -containing phagosomes independent of phagocytic ability. Deletion of CD82 in mice resulted in diminished fungicidal activity, increased 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 as compared with wild-type mice. Furthermore, patient -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 .