Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis.
Mycobacterium tuberculosis infection is a continuing global health crisis that kills 2 million people each year. Although the structurally diverse lipids of the M. tuberculosis cell envelope each have non-redundant roles in virulence or persistence, the molecular mechanisms regulating cell envelope composition in M. tuberculosis are undefined. In higher eukaryotes, membrane composition is controlled by site two protease (S2P)-mediated cleavage of sterol regulatory element binding proteins, membrane-bound transcription factors that control lipid biosynthesis. S2P is the founding member of a widely distributed family of membrane metalloproteases that cleave substrate proteins within transmembrane segments. Here we show that a previously uncharacterized M. tuberculosis S2P homologue (Rv2869c) regulates M. tuberculosis cell envelope composition, growth in vivo and persistence in vivo. These results establish that regulated intramembrane proteolysis is a conserved mechanism controlling membrane composition in prokaryotes and show that this proteolysis is a proximal regulator of cell envelope virulence determinants in M. tuberculosis.
Makinoshima
Hideki
H
Immunology Program, Sloan-Kettering Institute, New York, New York 10021, USA.
Glickman
Michael S
MS
D000818:Animals; D002455:Cell Division; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000166:cytology* / Q000254:growth & development / Q000472:pathogenicity*; D009171:Mycolic Acids / Q000032:analysis / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D014376:Tuberculosis / Q000821:virology; D014774:Virulence / Q000502:physiology
D009171:Mycolic Acids; D010447:Peptide Hydrolases