The role of site-2-proteases in bacteria: a review on physiology, virulence, and therapeutic potential

Abstract

Site-2-proteases are a class of intramembrane proteases involved in regulated intramembrane proteolysis. Regulated intramembrane proteolysis is a highly conserved signaling mechanism, which commonly involves sequential digestion of an anti-sigma factor by a site-1- and site-2-protease in response to external stimuli, resulting in an adaptive transcriptional response. Variation of this signaling cascade continues to emerge as the role of site-2-proteases in bacteria continues to be explored. Site-2-proteases are highly conserved among bacteria and play a key role in multiple processes including iron uptake, stress response and pheromone production. Additionally, an increasing number of site-2-proteases have been found to play a pivotal role in the virulence properties of multiple human pathogens, such as alginate production in Pseudomonas aeruginosa, toxin production in Vibrio cholerae, resistance to lysozyme in enterococci and antimicrobials in several Bacillus spp, and cell-envelope lipid composition in Mycobacterium tuberculosis. The prominent role of site-2-proteases in bacterial pathogenicity highlights the potential of site-2-proteases as novel targets for therapeutic intervention. In this review, we summarize the role of site-2-proteases in bacterial physiology and virulence, as well as evaluate the therapeutic potential of site-2-proteases.

Revisiting the Multifaceted Roles of Bacteriocins

“…In addition, it is known that proteins involved in regulatory pathways are directly influenced by bacteriocins. For instance, the leaderless LsbB family of bacteriocins targets the membrane-bound protease RseP [ 59 ] which serves as a key regulator for the stress response through the regulatory intramembrane proteolysis cascade across bacteria [ 57 , 58 ]. Upon bacteriocin exposure, resistant enterococci acquire mutations in the site-2 protease rseP rendering them with an altered stress response capability [ 59 ].…”

Lactiplantibacillus plantarum as a novel platform for production and purification of integral membrane proteins using RseP as the benchmark

“…RseP is a membrane-embedded metalloprotease involved in regulated intramembrane proteolysis (RIP), which is a widely distributed signaling mechanism used by bacteria to control a diverse array of cellular processes, including stress response, nutrient uptake, and virulence 32 – 36 . Due to its prominent role in bacterial physiology and virulence, RseP is considered an attractive antimicrobial target 37 , 38 . RseP of selected Gram-positive bacteria acts as a receptor for a specific group of bacteriocins known as the LsbB-family, further highlighting RseP as an potential antimicrobial target 39 – 43 .…”