Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells

Isamu Matsunaga, Apoorva Bhatt, David C. Young, Tan Yun Cheng, Stephen J. Eyles, Gurdyal S. Besra, Volker Briken, Steven A. Porcelli, Catherine E. Costello, William R. Jacobs, D. Branch Moody

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

CD1c-mediated T cells are activated by a mycobacterial phospholipid antigen whose carbohydrate structure precisely corresponds to mammalian mannosyl β-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.

Original languageEnglish (US)
Pages (from-to)1559-1569
Number of pages11
JournalJournal of Experimental Medicine
Volume200
Issue number12
DOIs
StatePublished - Dec 20 2004

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Keywords

  • CD1 antigens
  • Lipids
  • Monosaccharides
  • Polyisoprenyl phosphate
  • Polyketide synthase
  • Tuberculosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Matsunaga, I., Bhatt, A., Young, D. C., Cheng, T. Y., Eyles, S. J., Besra, G. S., Briken, V., Porcelli, S. A., Costello, C. E., Jacobs, W. R., & Moody, D. B. (2004). Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. Journal of Experimental Medicine, 200(12), 1559-1569. https://doi.org/10.1084/jem.20041429