M. tuberculosis intramembrane protease Rip1 controls transcription through three anti-sigma factor substrates

Immunology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Molecular Microbiology (Impact Factor: 4.42). 08/2010; 77(3):605-17. DOI: 10.1111/j.1365-2958.2010.07232.x
Source: PubMed


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.

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    • "The membrane spanning S2P proteases are involved in unleashing ECF s factors by proteolytic processing of their cognate anti-s factors, after the anti-s has been cleaved by a 'Site 1' protease. Rip1 has at least three different anti-s factor substrates (Sig K, M and L), enabling it to regulate several downstream pathways including defence against oxidative stress or the control of lipid metabolism (Sklar et al., 2010). It is not clear how S2P substrate specificity is achieved, in particular why substrates are only recognized after Site 1 cleavage. "
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