Tetraspanin CD82 Organizes Dectin-1 into Signaling Domains to Mediate Cellular Responses to <i>Candida albicans</i>

Tam, Jenny M.; Reedy, Jennifer L.; Lukason, Daniel P; Kuna, Sunnie G; Acharya, Mridu; Khan, Nida S.; Negoro, Paige; Xu, Shuying; Ward, Rebecca; Feldman, Michael B.; Dutko, Richard A.; Jeffery, Jane; Sokolovska, Anna; Wivagg, Carl N.; Naour, François Le; Matzaraki, Vasiliki; Garner, Edward B.; Xavier, Ramnik J.; Kumar, Vinod; Veerdonk, Frank L. van de; Netea, Mihai G.; Miranti, Cindy K.; Mansour, Michael K.; Vyas, Jatin M.

doi:10.4049/jimmunol.1801384

Cited by 30 publications

(35 citation statements)

References 62 publications

(78 reference statements)

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“…response (54)(55)(56). We recently reported that CD82 mediates dectin-1 clustering and enables robust downstream signaling (34). The tetraspanin CD37 interacts with dectin-1 to regulate surface expression in immune cells (48).…”

Section: Discussionmentioning

confidence: 99%

CD82 controls CpG‐dependent TLR9 signaling

et al. 2019

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The tetraspanin CD82 is a potent suppressor of tumor metastasis and regulates several processes including signal transduction, cell adhesion, motility, and aggregation. However, the mechanisms by which CD82 participates in innate immunity are unknown. We report that CD82 is a key regulator of TLR9 trafficking and signaling. TLR9 recognizes unmethylated cytosine‐phosphate‐guanine (CpG) motifs present in viral, bacterial, and fungal DNA. We demonstrate that TLR9 and CD82 associate in macrophages, which occurs in the endoplasmic reticulum (ER) and post‐ER. Moreover, CD82 is essential for TLR9‐dependent myddosome formation in response to CpG stimulation. Finally, CD82 modulates TLR9‐dependent NF‐αB nuclear translocation, which is critical for inflammatory cytokine production. To our knowledge, this is the first time a tetraspanin has been implicated as a key regulator of TLR signaling. Collectively, our study demonstrates that CD82 is a specific regulator of TLR9 signaling, which may be critical in cancer immunotherapy approaches and coordinating the innate immune response to pathogens.—Khan, N. S., Lukason, D. P., Feliu, M., Ward, R. A., Lord, A. K., Reedy, J. L., Ramirez‐Ortiz, Z. G., Tam, J. M., Kasperkovitz, P. V., Negoro, P. E., Vyas, T. D., Xu, S., Brinkmann, M. M., Acharaya, M., Artavanis‐Tsakonas, K., Frickel, E.‐M., Becker, C. E., Dagher, Z., Kim, Y.‐M., Latz, E., Ploegh, H. L., Mansour, M. K., Miranti, C. K., Levitz, S. M., Vyas, J. M. CD82 controls CpG‐dependent TLR9 signaling. FASEB J. 33, 12500–12514 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

CD82 controls CpG‐dependent TLR9 signaling

et al. 2019

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“…Next, we examined whether the defects in ROS affected the fungal killing ability by Skap2-/- DIV neutrophils. DIV neutrophils were incubated with C. glabrata for 24 hours, or C. albicans for 2 hours, and then fungal survival was measured using the PrestoBlue viability dye conversion (Xu et al, 2018, Tam et al, 2019). Compared to WT, Skap2-/- DIV neutrophils demonstrated significantly decreased fungicidal activity after infection with C. glabrata (Figure 5D-E) while infection with C. albicans typically also led to a decrease in fungal killing in 4 out of 5 experiments (Figure 5D, F).…”

Section: Resultsmentioning

confidence: 99%

“…The PrestoBlue assay kit (Thermo Fisher) was used to measure fungal viability following co-culture with WT and Skap2-/- DIV neutrophils (Tam et al, 2019, Xu et al, 2018, Negoro et al, 2020). DIV neutrophils in cRPMI were plated in triplicate 96-well non-tissue culture treated plates at a density of 1 × 10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin andCandidastimulation

Nguyen

Xu²,

Bunnell³

et al. 2021

Preprint

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Signaling cascades that convert the recognition of pathogens to efficient inflammatory responses by immune cells, specifically neutrophils, are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following stimulation by integrins, formyl peptide receptors and gram-negative bacteria Klebsiella pneumoniae and Yersinia pseudotuberculosis in vitro (Nguyen et al., 2020, Shaban et al., 2020, Boras et al., 2017). SKAP2 is also required for the host defense against K. pneumoniae and Capital Greek DeltayopH Y. pseudotuberculosis infection in vivo in mouse models (Shaban et al., 2020, Nguyen et al., 2020). Another class of pattern recognition receptors (PRR) is the C-type lectin receptors (CLR), such as Dectin-1, Dectin-2 and Mincle, that are critical to trigger innate immune responses. Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 is crucial for maximal ROS response to purified CLR agonists and to the fungal pathogens Candida glabrata and C. albicans, as well as for robust killing of C. glabrata. Skap2-/- murine neutrophils failed to generate ROS and exhibited reduced cellular adhesion in response to trehalose-6,6-dibehenate (TDB), furfurman, and curdlan, Mincle, Dectin-2, and Dectin-1 agonists, respectively. TDB, furfurman, and curdlan stimulation also led to SKAP2-independent integrin conformational changes, showing that inside-out signaling by these CLRs to integrin occurs in the absence of SKAP2. Pyk2 phosphorylation was significantly reduced after infection with C. glabrata in Skap2-/- neutrophils, while Syk phosphorylation was unaffected by the loss of SKAP2. These data strengthen the importance of SKAP2 in the activation of neutrophil ROS production by PRRs to include CLRs and extend the role of SKAP2 in host defense beyond antibacterial immunity to include Candida species.

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“…Recent reports have detailed a mechanism whereby decreased Dectin-1 signaling confers risk of candidemia. CD82 is involved in the clustering of Dectin-1 receptors, and the efficient activation of intracellular signaling upon ligand binding (Tam et al, 2019). Variants in CD82 are associated with both candidemia risk and decreased cytokine production upon stimulation with fungal ligands (Tam et al, 2019).…”

Section: Opportunistic Mucosal Infections Bymentioning

confidence: 99%

“…CD82 is involved in the clustering of Dectin-1 receptors, and the efficient activation of intracellular signaling upon ligand binding (Tam et al, 2019). Variants in CD82 are associated with both candidemia risk and decreased cytokine production upon stimulation with fungal ligands (Tam et al, 2019). It is less clear if there is a role for variants in CLEC7A, the gene encoding Dectin-1.…”

Section: Opportunistic Mucosal Infections Bymentioning

confidence: 99%

Advances in Understanding Human Genetic Variations That Influence Innate Immunity to Fungi

Merkhofer

Klein

2020

Front. Cell. Infect. Microbiol.

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Fungi are ubiquitous. Yet, despite our frequent exposure to commensal fungi of the normal mammalian microbiota and environmental fungi, serious, systemic fungal infections are rare in the general population. Few, if any, fungi are obligate pathogens that rely on infection of mammalian hosts to complete their lifecycle; however, many fungal species are able to cause disease under select conditions. The distinction between fungal saprophyte, commensal, and pathogen is artificial and heavily determined by the ability of an individual host's immune system to limit infection. Dramatic examples of commensal fungi acting as opportunistic pathogens are seen in hosts that are immune compromised due to congenital or acquired immune deficiency. Genetic variants that lead to immunological susceptibility to fungi have long been sought and recognized. Decreased myeloperoxidase activity in neutrophils was first reported as a mechanism for susceptibility to Candida infection in 1969. The ability to detect genetic variants and mutations that lead to rare or subtle susceptibilities has improved with techniques such as single nucleotide polymorphism (SNP) microarrays, whole exome sequencing (WES), and whole genome sequencing (WGS). Still, these approaches have been limited by logistical considerations and cost, and they have been applied primarily to Mendelian impairments in anti-fungal responses. For example, loss-of-function mutations in CARD9 were discovered by studying an extended family with a history of fungal infection. While discovery of such mutations furthers the understanding of human antifungal immunity, major Mendelian susceptibility loci are unlikely to explain genetic disparities in the rate or severity of fungal infection on the population level. Recent work using unbiased techniques has revealed, for example, polygenic mechanisms contributing to candidiasis. Understanding the genetic underpinnings of susceptibility to fungal infections will be a powerful tool in the age of personalized medicine. Future application of this knowledge may enable targeted health interventions for susceptible individuals, and guide clinical decision making based on a patient's individual susceptibility profile.

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

Cited by 30 publications

References 62 publications

CD82 controls CpG‐dependent TLR9 signaling

CD82 controls CpG‐dependent TLR9 signaling

Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin andCandidastimulation

Advances in Understanding Human Genetic Variations That Influence Innate Immunity to Fungi

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