Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis : Nature:
Mycobacterium tuberculosis infection is a continuing global health crisis that kills 2 million people each year1. Although the structurally diverse lipids of the M. tuberculosis cell envelope each have non-redundant roles in virulence or persistence2, 3, 4, 5, 6, 7, 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 proteins8, 9, membrane-bound transcription factors that control lipid biosynthesis. S2P is the founding member of a widely distributed family of membrane metalloproteases10, 11 that cleave substrate proteins within transmembrane segments12. 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.
A protein which occurs homologously in prokaryotes and eukaryotes has been co-opted into various processes in the cell. Understanding its operation in an infectious agent may lead to a better treatment for TB, and a better understanding of lipid metabolism in eukaryotes (like you and me).