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.
Converse
Scott E
SE
Department of Microbiology and Immunology, G.W. Hooper Foundation, University of California, San Francisco 94143, USA.
Mougous
Joseph D
JD
Leavell
Michael D
MD
Leary
Julie A
JA
Bertozzi
Carolyn R
CR
Cox
Jeffery S
JS
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