Mycolic Acids Constitute a Scaffold for Mycobacterial Lipid Antigens Stimulating CD1-Restricted T Cells

Layre, Emilie; Collmann, Anthony; Bastian, Max; Mariotti, Sabrina; Czaplicki, Jerzy; Prandi, Jacques; Mori, Lucia; Stenger, Steffen; Libero, Gennaro De; Puzo, Germain; Gilleron, Martine

doi:10.1016/j.chembiol.2008.11.008

Cited by 133 publications

(136 citation statements)

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“…Glycerol can leave the cell by passive or facilitated diffusion, serve as an osmolyte, or be used as a central building block in secondary metabolite or lipid antigen biosynthesis. For example, Layre and colleagues described the discovery of a glycerol-based lipid antigen, glycerol monomycolate, in M. tuberculosis (30). In addition, diarabinosyl glycerol dimycolate has also been described in M. tuberculosis (31).…”

Section: Resultsmentioning

confidence: 99%

Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis

Larrouy-Maumus

Biswas

Hunt

et al. 2013

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

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Functional assignment of enzymes encoded by the Mycobacterium tuberculosis genome is largely incomplete despite recent advances in genomics and bioinformatics. Here, we applied an activitybased metabolomic profiling method to assign function to a unique phosphatase, Rv1692. In contrast to its annotation as a nucleotide phosphatase, metabolomic profiling and kinetic characterization indicate that Rv1692 is a D,L-glycerol 3-phosphate phosphatase. Crystal structures of Rv1692 reveal a unique architecture, a fusion of a predicted haloacid dehalogenase fold with a previously unidentified GCN5-related N-acetyltransferase region.Although not directly involved in acetyl transfer, or regulation of enzymatic activity in vitro, this GCN5-related N-acetyltransferase region is critical for the solubility of the phosphatase. Structural and biochemical analysis shows that the active site features are adapted for recognition of small polyol phosphates, and not nucleotide substrates. Functional assignment and metabolomic studies of M. tuberculosis lacking rv1692 demonstrate that Rv1692 is the final enzyme involved in glycerophospholipid recycling/catabolism, a pathway not previously described in M. tuberculosis.haloacid dehalogenase superfamily | enzyme function | pathway discovery E ach year, 1.4 million people succumb to tuberculosis, making Mycobacterium tuberculosis the deadliest bacterium affecting mankind (1). In addition, the dissemination of strains resistant to several antibiotics underscores the need for better understanding of this pathogen and for the development of novel vaccines and therapeutics (2, 3). Our approach to elucidating the unique pervasiveness of M. tuberculosis is through comprehensive discovery and characterization of metabolic pathways, as metabolism underlies survival of the bacteria both inside and outside the host and can contribute to phenotypic and genetic drug resistance.The M. tuberculosis genome encodes for 4,043 genes, of which 3,933 encode proteins (4, 5). Many genes with essential functions, such as DNA replication, protein and RNA synthesis, and cell-division, have close homologs in other bacteria, and their functions are annotated largely on the basis of analysis of their counterparts. However, functions of at least one-third of the genes are unknown or putative (4). In particular, little is known about genes that are not conserved or conditionally important. Characterization of such genes presents a daunting task. M. tuberculosis is thought to be subjected to a myriad of conditions during its life cycle in the host, such as low pH, reactive oxygen and nitrogen species, and so on (6, 7). Understanding how M. tuberculosis adapts to and even thrives in such diverse environments is critical to our understanding of the pathology itself and for the discovery of novel therapeutics to treat tuberculosis.We applied an innovative, activity-based metabolomic profiling (ABMP) approach to assign function to orphan (without a priori known substrates/products) mycobacterial enzymes and to discover unk...

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Section: Resultsmentioning

confidence: 99%

Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis

Larrouy-Maumus

Biswas

Hunt

et al. 2013

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

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“…CD1b has the most voluminous and intricate groove, being composed of A′, C′, and F′ pockets and a T′ tunnel that interconnects the deep ends of A′ and F′ pockets (6). In agreement with groove structural complexity, human CD1b presents the greatest diversity of antigenic structures among CD1 proteins, including mycobacterial lipoarabinomannans and phosphatidylinositol mannosides (7-9), diacylsulfoglycolipids (Ac 2 SGL) (10), mycolic acids (MA) (11), glucose-and glycerolmonomycolates (GMM and GroMM, respectively) (12,13), and self-lipids such as GM1 gangliosides (14) and sulfatides (15). The polar heads of these antigens vary in size from the small carboxylic group of MA to the pentasaccharide of GM1 or potentially larger structures in lipoarabinomannans.…”

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confidence: 88%

Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids

Garcia-Alles

Collmann

Versluis

et al. 2011

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

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The mechanisms permitting nonpolymorphic CD1 molecules to present lipid antigens that differ considerably in polar head and aliphatic tails remain elusive. It is also unclear why hydrophobic motifs in the aliphatic tails of some antigens, which presumably embed inside CD1 pockets, contribute to determinants for T-cell recognition. The 1.9-Å crystal structure of an active complex of CD1b and a mycobacterial diacylsulfoglycolipid presented here provides some clues. Upon antigen binding, endogenous spacers of CD1b, which consist of a mixture of diradylglycerols, moved considerably within the lipid-binding groove. Spacer displacement was accompanied by F' pocket closure and an extensive rearrangement of residues exposed to T-cell receptors. Such structural reorganization resulted in reduction of the A' pocket capacity and led to incomplete embedding of the methyl-ramified portion of the phthioceranoyl chain of the antigen, explaining why such hydrophobic motifs are critical for T-cell receptor recognition. Mutagenesis experiments supported the functional importance of the observed structural alterations for T-cell stimulation. Overall, our data delineate a complex molecular mechanism combining spacer repositioning and ligandinduced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.three-dimensional structure | groove shrinking | diacylglycerol endogenous ligand | T lymphocyte activation | CD1b mutant transfectant T lymphocytes have developed the capacity to recognize as antigens a large variety of molecules including peptides, (glyco)lipids, and phosphorylated metabolites (1). Specific recognition of peptides or lipids by T-cell receptors (TCR) occurs when these molecules form antigenic complexes with dedicated antigen-presenting molecules belonging to MHC or CD1 families, respectively. Diversity has forced the immune system to develop appropriate strategies to present antigens in immunogenic form. Polymorphic MHC molecules cope with the peptide repertoire by constraining the ligand conformational space (2). Less clear is how the immune system adapts to the large glycolipid antigenic range and forms antigenic complexes using the functionally nonpolymorphic CD1 molecules.Human antigen-presenting cells (APC) display the CD1a, CD1b, CD1c, and CD1d proteins on their plasma membranes (1, 3). CD1 ectodomains consist of a heavy chain, which folds into three extracellular domains (α1-α3) noncovalently associated with β2-microglobulin (4). Antigen-binding grooves nestle between the α1 and α2 domains and are mostly lined by hydrophobic residues. This allows the antigenic lipids to be anchored via their hydrophobic chains, so that polar motifs protrude toward the aqueous milieu. Consequently, polar heads but not hydrophobic tails are assumed to establish stimulatory contacts with TCRs. Nevertheless, modifications in the lipid chains may also indirectly impact on TCR recognition (5).The number, shape, and conn...

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“…However, it is increasingly recognized that unconventional epitopes may also play a role in the antimycobacterial immune response. So far, pyrophosphate Ags recognized by butyrophilin-restricted g-d T cells (15), and CD1-restricted lipids and glycolipids, such as monomycolates (16,17), diacylated sulphoglycolipid (18), or lipoarabinomannan (19), have been described as relevant Ags in this context. The recognition of lipids may be of particular importance for maintenance of the persistence state, because mycobacteria switch to a hypoxic lipid metabolism in the inner caseous region of the granuloma (20,21).…”

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confidence: 99%

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Kaufmann

Spohr

Battenfeld

et al. 2016

The Journal of Immunology

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A new class of highly antigenic, MHC-II–restricted mycobacterial lipopeptides that are recognized by CD4-positive T lymphocytes of Mycobacterium tuberculosis–infected humans has recently been described. To investigate the relevance of this novel class of mycobacterial Ags in the context of experimental bacille Calmette-Guérin (BCG) vaccination, Ag-specific T cell responses to mycobacterial lipid and lipopeptide-enriched Ag preparations were analyzed in immunized guinea pigs. Lipid and lipopeptide preparations as well as complex Ag mixtures, such as tuberculin, mycobacterial lysates, and culture supernatants, all induced a similar level of T cell proliferation. The hypothesis that lipopeptide-specific T cells dominate the early BCG-induced T cell response was corroborated in restimulation assays by the observation that Ag-expanded T cells specifically responded to the lipopeptide preparation. A comparative analysis of the responses to Ag preparations from different mycobacterial species revealed that the antigenic lipopeptides are specific for strains of the M. tuberculosis complex. Their intriguing conservation in pathogenic tuberculous bacteria and the fact that these highly immunogenic Ags seem to be actively released during in vitro culture and intracellular infection prompt the urgent question about their role in the fine-tuned interplay between the pathogen and its mammalian host, in particular with regard to BCG vaccination strategies.

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Mycolic Acids Constitute a Scaffold for Mycobacterial Lipid Antigens Stimulating CD1-Restricted T Cells

Cited by 133 publications

References 41 publications

Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis

Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis

Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

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