MHCII glycosylation modulates <i>Bacteroides fragilis</i> carbohydrate antigen presentation

Ryan, Sean O.; Bonomo, Jason A.; Zhao, Fan; Cobb, Brian A.

doi:10.1084/jem.20100508

Cited by 45 publications

(69 citation statements)

References 45 publications

(119 reference statements)

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“…Upon neutralization of either charge, the antigen is rendered inactive (6,11,12) due in part to conformational changes that result in loss of MHCII binding (12). Interestingly, we have also found that the glycosylation pattern on MHCII directly impacts MHCII binding by PSA, likely through carbohydrate-carbohydrate interactions with conserved N-linked glycans on MHCII (13)(14)(15). Despite these advances in our understanding of MHCII-mediated presentation of these unusual antigens, almost nothing is known about their recognition by their cognate T cell.…”

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confidence: 64%

Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

Johnson

Jones

Cobb

2015

Journal of Biological Chemistry

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confidence: 64%

Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

Johnson

Jones

Cobb

2015

Journal of Biological Chemistry

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“…S3). The N-glycans on class II are thought to play a role in proper folding of nascent molecules (31), in protease resistance (32), in facilitating optimal receptor geometry for APC/T-cell communication (33), and, most recently, in presentation of particular carbohydrate antigens (34). We found that the α1 domain N-glycan at szDOvαN79, near α-chain/β-chain interface and homologous to αN78 in conventional MHC class II, influences the aggregation state of the molecule (Fig.…”

Section: Effect Of Mutations In the Dmβ2 Domain On Interaction With Domentioning

confidence: 99%

Mapping the HLA-DO/HLA-DM complex by FRET and mutagenesis

Yoon

Macmillan

Mortimer

et al. 2012

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

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HLA-DO (DO) is a nonclassic class II heterodimer that inhibits the action of the class II peptide exchange catalyst, HLA-DM (DM), and influences DM localization within late endosomes and exosomes. In addition, DM acts as a chaperone for DO and is required for its egress from the endoplasmic reticulum (ER). These reciprocal functions are based on direct DO/DM binding, but the topology of DO/DM complexes is not known, in part, because of technical limitations stemming from DO instability. We generated two variants of recombinant soluble DO with increased stability [zippered DOαP11A (szDOv) and chimeric sDO-Fc] and confirmed their conformational integrity and ability to inhibit DM. Notably, we found that our constructs, as well as wild-type sDO, are inhibitory in the full pH range where DM is active (4.7 to ∼6.0). To probe the nature of DO/DM complexes, we used intermolecular fluorescence resonance energy transfer (FRET) and mutagenesis and identified a lateral surface spanning the α1 and α2 domains of szDO as the apparent binding site for sDM. We also analyzed several sDM mutants for binding to szDOv and susceptibility to DO inhibition. Results of these assays identified a region of DM important for interaction with DO. Collectively, our data define a putative binding surface and an overall orientation of the szDOv/ sDM complex and have implications for the mechanism of DO inhibition of DM.antigen processing | antigen presentation | MHC class II M ajor histocompatibility complex (MHC) class II molecules present peptides on the antigen-presenting cell (APC) surface to sensitize CD4 + lymphocytes. The class II presentation pathway is well-characterized and includes roles for three accessory molecules: invariant chain (Ii), HLA-DM (DM), and HLA-DO (DO) (1). Newly synthesized MHC class II molecules bind to Ii in the ER. A trafficking signal in the cytoplasmic domain of invariant chain directs the complex to late endosomal compartments (2, 3), called MIIC (MHC II containing compartments). The invariant chain (Ii) is proteolytically degraded in this low-pH environment, leaving a nested set of invariant chain fragments, CLIPs (class II-associated invariant chain peptides), in the class II peptide-binding groove (4). CLIP is ultimately exchanged for antigenic peptides by DM, a nonclassic MHC class II molecule, which further influences peptide selection in a process termed "peptide editing" (5-10). DM also stabilizes empty MHC class II to maintain a peptide receptive structure; otherwise, empty MHC class II proteins become peptide averse (11).DO, another nonclassic MHC class II αβ heterodimer, first was described as an inhibitor of DM function, because overexpression of DO in human cells increased levels of CLIP-bound class II molecules (12, 13). In vitro evidence most often corroborated the view of DO as a negative modulator of DM (12,14). Results suggesting that DO inhibition of DM is robust at early endosomal pH (6.0-6.5) and attenuated at the lower pH (4.5-5.0) of late endosomal/lysosomal MHC II containing compartments...

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“…Asparagine-linked glycosylation is one of the most common post-translational modifications of eukaryotic proteins (14). In general, the role of N-linked glycosylation in folding, secretion, and resistance to proteolysis is understood for several proteins (15,16), and several examples have exemplified the crucial role of N-glycans in protein function, such as bacterial recognition (17), intracellular signaling (18), and antigen binding and presentation (19).…”

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Endo-β-N-acetylglucosaminidases from Infant Gut-associated Bifidobacteria Release Complex N-glycans from Human Milk Glycoproteins

Garrido

Nwosu

Ruíz-Moyano

et al. 2012

Molecular & Cellular Proteomics

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Breastfeeding is one of the main factors guiding the composition of the infant gut microbiota in the first months of life. This process is shaped in part by the high amounts of human milk oligosaccharides that serve as a carbon source for saccharolytic bacteria such as Bifidobacterium species. Infant-borne bifidobacteria have developed various molecular strategies for utilizing these oligosaccharides as a carbon source. We hypothesized that these species also interact with N-glycans found in host glycoproteins that are structurally similar to free oligosaccharides in human milk. Endo-␤-Nacetylglucosaminidases were identified in certain isolates of Bifidobacterium longum subsp. longum, B. longum subsp. infantis, and Bifidobacterium breve, and their presence correlated with the ability of these strains to deglycosylate glycoproteins. An endoglycosidase from B. infantis ATCC 15697, EndoBI-1, was active toward all major types of N-linked glycans found in glycosylated proteins. Its activity was not affected by core fucosylation or extensive fucosylation, antenna number, or sialylation, releasing several N-glycans from human lactoferrin and immunoglobulins A and G. Extensive N-deglycosylation of whole breast milk was also observed after coincubation with this enzyme. Mutation of the active site of EndoBI-1 did not abolish binding to N-glycosylated proteins, and this mutant specifically recognized Man 3 GlcNAc 2 (␣1-6Fuc), the core structure of human N-glycans. EndoBI-1 is constitutively expressed in B. infantis, and incubation of the bacterium with human or bovine lactoferrin led to the induction of genes associated to import and consumption of human milk oligosaccharides, suggesting linked regulatory mechanisms among these glycans. This work reveals an unprecedented interaction of bifidobacteria with host

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MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation

Abstract: N-linked glycans on class II MHC molecules are required for the presentation of glycoantigens, but not peptide antigens.

Cited by 45 publications

References 45 publications

Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

Mapping the HLA-DO/HLA-DM complex by FRET and mutagenesis

Endo-β-N-acetylglucosaminidases from Infant Gut-associated Bifidobacteria Release Complex N-glycans from Human Milk Glycoproteins

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