Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis

Publisher Website
Google Scholar
Abstract
Many of the virulence determinants of Mycobacterium tuberculosis are lipids and glycolipids of the cell envelope. Now at last a mechanism that controls cell envelope composition — and in vivo pathogenesis — has been uncovered. It is regulated intramembrane proteolysis, a type of lipid regulation also used by mammals and bacteria. RIP may be an attractive pathway to target for development of new antituberculosis antibiotics. 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.

This publication has 30 references indexed in Scilit: