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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 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.

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Figure 1: Rv2869c is a non-essential intramembrane cleaving protease (iCLIP) of pathogenic mycobacteria.
Figure 2: Rv2869c and its proteolytic activity are required for mycobacterial cording.
Figure 3: Rv2869c transcriptionally regulates the extractable mycolic acid composition of the mycobacterial cell envelope.
Figure 4: Rv2869c is required for both M. tuberculosis replication and persistence in mice.


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We thank P. Bongiorno and F. Gao for technical support; V. Rao, N. Serbina, P. Wong and N. Stephanou for discussions; and A. Viale and the Genomics Core Lab of the Memorial Sloan-Kettering Cancer Center for assistance with microarray experiments. M.S.G. is supported by an NIH grant, the Ellison Medical Foundation, and the Speakers Fund for Biomedical Research awarded by the City of New York.

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Correspondence to Michael S. Glickman.

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Makinoshima, H., Glickman, M. Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis. Nature 436, 406–409 (2005).

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