9.B.217. The Transmembrane PrsW Protease (PrsW) Family
The activation of the RNA polymerase sigma factor sigmaW in Bacillus subtilis is regulated by intramembrane proteolysis by a PrsW protease (Ellermeier and Losick 2006). SigmaW is activated by proteolytic destruction of the membrane-bound anti-sigmaW factor RsiW in response to antimicrobial peptides and other agents that damage the cell envelope. RsiW is destroyed by successive proteolytic events known as Site-1 and Site-2 cleavage. Site-2 cleavage is mediated by a member of the SpoIVFB-S2P family of intramembrane-acting metalloproteases, but the protease responsible for Site-1 cleavage is by PrsW (annotated YpdC) that is both necessary and sufficient for Site-1 cleavage of RsiW. Ellermeier and Losick 2006 identified residues important for proteolysis and a cluster of acidic residues involved in sensing antimicrobial peptides and cell envelope stress. Another membrane protease, RasP, when defective, causes defects in competence development, protein secretion and membrane protein production (Zweers et al. 2012). σV activation in B. subtilis is controlled by regulated intramembrane proteolysis and requires the site 2 protease RasP (Hastie et al. 2013). RasP, an intramembrane metalloprotease of Bacillus subtilis, cleaves both the stress response anti-sigma factors RsiW and RsiV as well as the cell division protein FtsL, and remnant signal peptides, within their transmembrane segments (Parrell et al. 2017). PrsW likely regulates the activation of the ECF σ factor CsfT in Clostridium difficile and controls the resistance of C. difficile to antimicrobial peptides (Ho and Ellermeier 2011). In Staphylococcus aureus, PrsS, a homologue of PrsW, and σS together mediate virulence and resistance to DNA damage and cell wall-targeting antibiotics via a common pathway (Krute et al. 2015).
PrsW proteases, the DUF2324 family and the γ-secretase subunit APH-1 proteins share four predicted core transmembrane segments and possess similar yet distinct sets of sequence motifs (Pei et al. 2011). Remote similarity between APH-1 and membrane proteases sheds light on APH-1's evolutionary origin and raises the possibility that APH-1 may possess proteolytic activity in the current or ancestral form of γ-secretase.