MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence.
Mycobacterium tuberculosis, the causative agent of human tuberculosis, is unique among bacterial pathogens in that it displays a wide array of complex lipids and lipoglycans on its cell surface. One of the more remarkable lipids is a sulfated glycolipid, termed sulfolipid-1 (SL-1), which is thought to mediate specific host-pathogen interactions during infection. However, a direct role for SL-1 in M. tuberculosis virulence has not been established. Here we show that MmpL8, a member of a large family of predicted lipid transporters in M. tuberculosis, is required for SL-1 production. The accumulation of an SL-1 precursor, termed SL(1278), in mmpL8 mutant cells indicates that MmpL8 is necessary for an intermediate step in the SL-1 biosynthesis pathway. We use a novel fractionation procedure to demonstrate that SL-1 is present on the cell surface, whereas SL(1278) is found exclusively in more internal layers. Importantly, we show that mmpL8 mutants are attenuated for growth in a mouse model of tuberculosis. However, SL-1 per se is not required for establishing infection as pks2 mutants, which are defective in an earlier step in SL-1 biosynthesis, have no obvious growth defect. Thus, we hypothesize that either MmpL8 transports molecules in addition to SL-1 that mediate host-pathogen interactions or the accumulation of SL(1278) in mmpL8 mutant cells interferes with other pathways required for growth during the early stages of infection.
Department of Microbiology and Immunology, G.W. Hooper Foundation, University of California, San Francisco 94143, USA.
Scott E
SE
Converse
Joseph D
JD
Mougous
Michael D
MD
Leavell
Julie A
JA
Leary
Carolyn R
CR
Bertozzi
Jeffery S
JS
Cox
D001426:Bacterial Proteins / Q000378:metabolism*; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D004187:Disaccharides / Q000096:biosynthesis / Q000737:chemistry; D017353:Gene Deletion; D006017:Glycolipids / Q000096:biosynthesis* / Q000737:chemistry; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors
D001426:Bacterial Proteins; D002352:Carrier Proteins; D004187:Disaccharides; D006017:Glycolipids; D037521:Virulence Factors; C009355:sulfolipid I