The Journal of Experimental Medicine
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Published 20 December 2004. doi:10.1084/jem.20041429
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1559-1569
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Mycobacterium tuberculosis pks12 Produces a Novel Polyketide Presented by CD1c to T Cells

Isamu Matsunaga1, Apoorva Bhatt2,3, David C. Young1, Tan-Yun Cheng1, Stephen J. Eyles4, Gurdyal S. Besra5, Volker Briken3, Steven A. Porcelli3, Catherine E. Costello6, William R. Jacobs, Jr.2,3, and D. Branch Moody1

1 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
2 Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461
3 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
4 Polymer Science and Engineering, University of Massachusetts, Amherst, MA 01003
5 School of Biosciences, The University of Birmingham, Edgbaston B15 2TT, England, UK
6 Mass Spectrometry Resource, Boston University School of Medicine, Boston, MA 02118

Address correspondence to D. Branch Moody, Div. of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, One Jimmy Fund Way, Smith 514A, Boston, MA 02115. Phone: (617) 525-1037; Fax: (617) 525-1010; email: bmoody{at}rics.bwh.harvard.edu

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

Key Words: tuberculosis • CD1 antigens • polyketide synthase • polyisoprenyl phosphate monosaccharides • lipids

Abbreviations used in this paper: AT, acyltransferase; BCG, Bacille-Calmette-Guerin; CID, collisionally induced dissociation; DIM, phthiocerol dimycocerosate; ESI, electrospray ionization; FAS, fatty acid synthase; IPP, isopentenyl pyrophosphate; MPD, mannosyl-ß-1-phosphodolichol; MPI, mannosyl-ß-1-phosphoisoprenoid; MPM, mannosyl-ß-1-phoshomycoketide; MPP, mannosyl-ß-1-phosphopolyisoprenol; MS, mass spectrometry; PKS, polyketide synthase.


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