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Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2004 Dec 20; Vol. 200 (12), pp. 1559-69. - Publication Year :
- 2004
-
Abstract
- CD1c-mediated T cells are activated by a mycobacterial phospholipid antigen whose carbohydrate structure precisely corresponds to mammalian mannosyl beta-1-phosphodolichol (MPD), but contains an unusual lipid moiety. Here, we show that this T cell antigen is a member of a family of branched, alkane lipids that vary in length (C30-34) and are produced by medically important mycobacteria such as M. tuberculosis and M. bovis Bacille-Calmette-Guerin. The alkane moiety distinguished these mycobacterial lipid antigens from mammalian MPDs and was necessary for activation of CD1c-restricted T cells, but could not be accounted for by any known lipid biosynthetic pathway. Metabolic labeling and mass spectrometric analyses suggested a mechanism for elongating lipids using alternating C2 and C3 units, rather than C5 isopentenyl pyrophosphate. Inspection of the M. tuberculosis genome identified one candidate gene, pks12, which was predicted to encode the largest protein in M. tuberculosis, consisting of 12 catalytic domains that correspond to key steps in the proposed pathway. Genetic deletion and complementation showed that Pks12 was necessary for antigen production, but did not affect synthesis of true isoprenols. These studies establish the genetic and enzymatic basis for a previously unknown type of polyketide, designated mycoketide, which contains a lipidic pathogen-associated molecular pattern.
- Subjects :
- Antigen Presentation immunology
Bacterial Proteins immunology
Cells, Cultured
Fatty Acid Synthases immunology
Gene Deletion
Genetic Complementation Test
Glycolipids biosynthesis
Glycolipids chemistry
Glycolipids genetics
Humans
Lymphocyte Activation immunology
Macrolides chemistry
Mycobacterium bovis genetics
Mycobacterium bovis immunology
Mycobacterium tuberculosis chemistry
Mycobacterium tuberculosis immunology
Terpenes metabolism
Antigens, CD1 immunology
Bacterial Proteins genetics
Fatty Acid Synthases genetics
Glycolipids immunology
Macrolides immunology
Mycobacterium tuberculosis genetics
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1007
- Volume :
- 200
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 15611286
- Full Text :
- https://doi.org/10.1084/jem.20041429