A probable site-2 protease (S2P) that cleaves type-2 transmembrane proteins within their membrane-spanning domains. Degrades anti-sigma factors RskA, RslA and RsmA, releasing sigma factors SigK, SigL and SigM from the cellular membrane, activating signaling pathways. Does not act on RsdA. Regulates the composition of extractable mycolic acids in the cell envelope in response to changes in membrane fluidity. Mediates transcriptional regulation of mycolic acid biosynthetic genes in response to detergent. Probably also cleaves PbpB (PBP3, FtsI); this cleavage is inhibited by Wag31-PbpBI interaction. Regulated intramembrane proteolysis (RIP) occurs when an extracytoplasmic signal (possibly oxidative stress) triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning regulatory substrate protein (includes anti-sigma factors RskA, RslA, RsmA, and PbpB) is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, this entry), while cytoplasmic proteases finish degrading the regulatory protein, liberating the effector protein (ECF sigma factors SigK, SigL and SigM). Not essential. Altered processing of anti-sigma factors RskA, RslA and RslM. Cells have altered colony morphology, lacking cording associated with virulence. Down-regulates extractable alpha-mycolate synthesis 4.6-fold, methoxymycolates 3.5-fold and ketomycolates 2.3-fold; has no effect on covalently esterified cell wall mycolates. Decreased abundance of hexamannosylated phosphatidylinositol mannoside. Decreased abundance of rpfC. Impairment of bacterial growth in a mouse (C57BL/6) aerosol infection. Bacterial titers in the lung after 3 weeks of infection were about 100-fold lower than in the wild-type; by 22 weeks they are 10,000-fold lower in the lung and fully cleared from the liver. Belongs to the peptidase M50B family.