MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence.

Abstract

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.

• Authors: Scott E Converse, Joseph D Mougous, Michael D Leavell, Julie A Leary, Carolyn R Bertozzi, Jeffery S Cox
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 10 Pg. 6121-6 (May 13 2003) ISSN: 0027-8424 [Print] United States
• PMID: 12724526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bacterial Proteins
• Carrier Proteins
• Disaccharides
• Glycolipids
• Virulence Factors
• sulfolipid I

Topics

• Bacterial Proteins (metabolism)
• Carbohydrate Conformation
• Carbohydrate Sequence
• Carrier Proteins (metabolism)
• Disaccharides (biosynthesis, chemistry)
• Gene Deletion
• Glycolipids (biosynthesis, chemistry)
• Mutagenesis
• Mycobacterium tuberculosis (genetics, metabolism, pathogenicity)
• Virulence
• Virulence Factors