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M. tuberculosis intramembrane protease Rip1 controls transcription through three anti‐sigma factor substrates
Author(s) -
Sklar Joseph G.,
Makinoshima Hideki,
Schneider Jessica S.,
Glickman Michael S.
Publication year - 2010
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2010.07232.x
Subject(s) - biology , proteolysis , sigma factor , signal transduction , protease , transmembrane protein , microbiology and biotechnology , biochemistry , transcription factor , gene , enzyme , promoter , gene expression , receptor
Summary Regulated intramembrane proteolysis (RIP) is a mechanism of transmembrane signal transduction that functions through intramembrane proteolysis of substrates. We previously reported that the RIP metalloprotease Rv2869c (Rip1) is a determinant of Mycobacterium tuberculosis (Mtb) cell envelope composition and virulence, but the substrates of Rip1 were undefined. Here we show that Rip1 cleaves three transmembrane anti‐sigma factors: anti‐SigK, anti‐SigL and anti‐SigM, negative regulators of Sigma K, L and M. We show that transcriptional activation of katG in response to phenanthroline requires activation of SigK and SigL by Rip1 cleavage of anti‐SigK and anti‐SigL. We also demonstrate a Rip1‐dependent pathway that activates the genes for the mycolic acid biosynthetic enzyme KasA and the resuscitation promoting factor RpfC, but represses the bacterioferritin encoding gene bfrB . Regulation of these three genes by Rip1 is not reproduced by deletion of Sigma K, L or M, either indicating a requirement for multiple Rip1 substrates or additional arms of the Rip1 pathway. These results identify a branched proteolytic signal transduction system in which a single intramembrane protease cleaves three anti‐sigma factor substrates to control multiple downstream pathways involved in lipid biosynthesis and defence against oxidative stress.