期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 200, 期 12, 页码 1559-1569出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20041429
关键词
tuberculosis; CD1 antigens; polyketide synthase; polyisoprenyl phosphate monosaccharides; lipids
资金
- NCRR NIH HHS [RR10888, P41 RR010888] Funding Source: Medline
- NIAID NIH HHS [R01 AI049313, R37 AI026170, AI 49313, R01 AI026170, AI26170] Funding Source: Medline
- NIAMS NIH HHS [AR 48632, R01 AR048632] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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 C-2 and C-3 units, rather than C-5 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.
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