The N-terminal Domain of Drosophila Gram-negative Binding Protein 3 (GNBP3) Defines a Novel Family of Fungal Pattern Recognition Receptors

Mishima, Yumiko; Quintin, Jessica; Aimanianda, Vishukumar; Kellenberger, Christine; Coste, Franck; Clavaud, Cécile; Hétru, Charles; Hoffmann, Jules A.; Latgé, Jean‐Paul; Ferrandon, Dominique; Roussel, Alain

doi:10.1074/jbc.m109.034587

Cited by 55 publications

(82 citation statements)

References 52 publications

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“…Thus, the presence of the O-and N-linked mannosyl proteins at the Candida cell surface is required for proper priming, supposedly by aiding cell priming by an additional cell wall component. Of note, although, under aqueous conditions, long chains of purified b-glucan form a right-handed triple helical complex that is required for the proper binding to pattern recognition receptors (27)(28)(29), purified mannan might not have the required structure to be recognized by its receptor, offering an alternative explanation for the lack of priming induced by pure mannans. Different biological effects of mannans were reported, including induction of proinflammatory cytokines (19,30) and of IL-10 (31).…”

Section: Discussionmentioning

confidence: 99%

Candida albicans Primes TLR Cytokine Responses through a Dectin-1/Raf-1–Mediated Pathway

Ifrim¹,

Joosten²,

Kullberg³

et al. 2013

The Journal of Immunology

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The immune system is essential to maintain homeostasis with resident microbial populations, ensuring that the symbiotic host–microbial relationship is maintained. In parallel, commensal microbes significantly shape mammalian immunity at the host mucosal surface, as well as systemically. Candida albicans is an opportunistic pathogen that lives as a commensal on skin and mucosa of healthy individuals. Little is known about its capacity to modulate responses toward other microorganisms, such as colonizing bacteria (e.g., intestinal microorganisms). The aim of this study was to assess the cytokine production of PBMCs induced by commensal bacteria when these cells were primed by C. albicans. We show that C. albicans and β-1,3-glucan induce priming of human primary mononuclear cells and this leads to enhanced cytokine production upon in vitro stimulation with TLR ligands and bacterial commensals. This priming requires the β-1,3-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. In addition, although purified mannans cannot solely mediate the priming, the presence of mannosyl residues in the cell wall of C. albicans is nevertheless required. In conclusion, C. albicans is able to modify cytokine responses to TLR ligands and colonizing bacteria, which is likely to impact the inflammatory reaction during mucosal diseases.

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Section: Discussionmentioning

confidence: 99%

Candida albicans Primes TLR Cytokine Responses through a Dectin-1/Raf-1–Mediated Pathway

Ifrim¹,

Joosten²,

Kullberg³

et al. 2013

The Journal of Immunology

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“…Lys-type PG and ␤-1,3-glucan are specifically recognized by the PG recognition protein (PGRP)-SA⅐Gram-negative-binding protein 1 (GNBP1) complex and GNBP3, respectively. GNBPs are 50-kDa proteins with a C-terminal, 200-residue ␤-glucanase-like domain and an N-terminal, 100-residue domain reported to bind ␤-1,3-glucan (14). In contrast, the Imd pathway is activated primarily via PGRP-LC or PGRP-LE after recognition of DAP-type PG found in Gram-negative bacteria and Bacillus sp.…”

Section: Peptidoglycan (Pg)mentioning

confidence: 99%

Diversity of Innate Immune Recognition Mechanism for Bacterial Polymeric meso-Diaminopimelic Acid-type Peptidoglycan in Insects

Park

Kwon

et al. 2010

Journal of Biological Chemistry

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In Drosophila, the synthesis of antimicrobial peptides in response to microbial infections is under the control of the Toll and immune deficiency (Imd) signaling pathway. The Toll signaling pathway responds mainly to the lysine-type peptidoglycan of Gram-positive bacteria and fungal ␤-1,3-glucan, whereas the Imd pathway responds to the meso-diaminopimelic acid (DAP)-type peptidoglycan of Gram-negative bacteria and certain Gram-positive bacilli. Recently we determined the activation mechanism of a Toll signaling pathway biochemically using a large beetle, Tenebrio molitor. However, DAP-type peptidoglycan recognition mechanism and its signaling pathway are still unclear in the fly and beetle. Here, we show that polymeric DAP-type peptidoglycan, but not its monomeric form, formed a complex with Tenebrio peptidoglycan recognition protein-SA, and this complex activated the three-step proteolytic cascade to produce processed Spätzle, a Toll receptor ligand, and induced Drosophila defensin-like antimicrobial peptide in Tenebrio larvae similarly to polymeric lysine-type peptidoglycan. Monomeric DAP-type peptidoglycan induced Drosophila diptericin-like antimicrobial peptide in Tenebrio hemocytes. In addition, both polymeric and monomeric DAP-type peptidoglycans induced expression of Tenebrio peptidoglycan recognition protein-SC2, which is DAP-type peptidoglycan-selective N-acetylmuramyl-L-alanine amidase that functions as a DAPtype peptidoglycan scavenger, appearing to function as a negative regulator of the DAP-type peptidoglycan signaling by cleaving DAP-type peptidoglycan in Tenebrio larvae. Taken together, these results demonstrate that molecular recognition mechanism for polymeric DAP-type peptidoglycan is different between Tenebrio larvae and Drosophila adults, providing biochemical evidences of biological diversity of innate immune responses in insects.

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“…The Toll receptor is activated by the Spätzle cytokine, following its proteolytic maturation into an active ligand by the Spätzle-processing enzyme (23). Gram-negative binding protein 3 (GNBP3) binds to fungal b-(1,3)-glucan and activates a proteolytic cascade that ultimately matures Spätzle through the Spätzle-processing enzyme (22,24). However, D. melanogaster does not solely rely on pattern recognition receptors (PRRs) to detect infections.…”

mentioning

confidence: 99%

The Drosophila Toll Pathway Controls but Does Not Clear Candida glabrata Infections

Quintin

Asmar

Matskevich

et al. 2013

The Journal of Immunology

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The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host.

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The N-terminal Domain of Drosophila Gram-negative Binding Protein 3 (GNBP3) Defines a Novel Family of Fungal Pattern Recognition Receptors

Cited by 55 publications

References 52 publications

Candida albicans Primes TLR Cytokine Responses through a Dectin-1/Raf-1–Mediated Pathway

Candida albicans Primes TLR Cytokine Responses through a Dectin-1/Raf-1–Mediated Pathway

Diversity of Innate Immune Recognition Mechanism for Bacterial Polymeric meso-Diaminopimelic Acid-type Peptidoglycan in Insects

The Drosophila Toll Pathway Controls but Does Not Clear Candida glabrata Infections

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