Identification of Distinct Ligands for the C-type Lectin Receptors Mincle and Dectin-2 in the Pathogenic Fungus Malassezia

Ishikawa, Tetsuaki; Itoh, Fumie; Yoshida, Sayumi; Saijo, Shinobu; Matsuzawa, T.; Gonoi, Tohru; Saito, Takashi; Okawa, Yoshio; Shibata, Nobuyuki; Miyamoto, Tomofumi; Yamasaki, Sho

doi:10.1016/j.chom.2013.03.008

Cited by 199 publications

(231 citation statements)

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“…A common Mincle ligand signature structure has been predicted based on a number of identified ligands (6,7,(33)(34)(35) in combination with the Mincle protein structure (9)(10)(11)(12). A polar head consisting of glucose or mannose and a hydrophobic chain appear to be the minimum requirement for ligand activity.…”

Section: Discussionmentioning

confidence: 99%

“…Given that glycolipids with longer FA have potent activities (10,11,34,35), epidermosides might be recognized by Mincle on dermal Mϕ/DCs and thereby modulate immune responses in skin. Interestingly, Mincle is involved in the immune response against fungi that causes skin disease (41) through the recognition of its unique glycolipids (7,42). It is tempting to speculate that both pathogen-derived and skinderived glycolipids contribute to disease onset or progression.…”

Section: Discussionmentioning

confidence: 99%

“…Mincle ligands have been reported to induce Th1 or Th17 or both Th1/Th17 responses (7,(60)(61)(62)(63). Although the precise molecular mechanisms underlying different Th responses via the same CLRs are presently unknown, the intensity of signaling through ITAMs may determine the type of responses (63)(64)(65)(66).…”

Section: Discussionmentioning

confidence: 99%

“…The 2B4-NFAT-GFP reporter cells expressing Mincle, MCL, Dectin-2, or DCAR were prepared as previously described (5,7,62). HEK293-based NF-κB reporter cells expressing mMincle were obtained from InvivoGen.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, Mincle recognizes pathogens, including mycobacteria through bipolar glycolipids, such as trehalose 6,6′-dimycolate (TDM), which act as pathogen-associated molecular patterns (6)(7)(8). Structural analysis of the Mincle protein has revealed how its unique ligandbinding site is suitable for glycolipid recognition (9)(10)(11)(12).…”

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confidence: 99%

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Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

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