Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells.
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.
Matsunaga
Isamu
I
Div. of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, One Jimmy Fund Way, Smith 514A, Boston, MA 02115, USA.
Bhatt
Apoorva
A
Young
David C
DC
Cheng
Tan-Yun
TY
Eyles
Stephen J
SJ
Besra
Gurdyal S
GS
Briken
Volker
V
Porcelli
Steven A
SA
Costello
Catherine E
CE
Jacobs
William R
WR
Moody
D Branch
DB
D017951:Antigen Presentation / Q000276:immunology; D018949:Antigens, CD1 / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000276:immunology; D017353:Gene Deletion; D005816:Genetic Complementation Test; D006017:Glycolipids / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D018942:Macrolides / Q000737:chemistry / Q000276:immunology*; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013729:Terpenes / Q000378:metabolism
D018949:Antigens, CD1; D001426:Bacterial Proteins; D006017:Glycolipids; D018942:Macrolides; D013729:Terpenes; D064429:Fatty Acid Synthases; C497999:Pks12 protein, Mycobacterium tuberculosis; C429525:Pks2 protein, Mycobacterium tuberculosis