Function of site-2 proteases in bacteria and bacterial pathogens

Abstract

Site-2 Proteases (S2Ps) are a class of intramembrane metalloproteases named after the founding member of this protein family, human S2P, which cleaves Sterol Regulatory Element Binding Proteins which control cholesterol and fatty acid biosynthesis. S2Ps are widely distributed in bacteria and participate in diverse pathways that control such diverse functions as membrane integrity, sporulation, lipid biosynthesis, pheromone production, virulence, and others. The most common signaling mechanism mediated by S2Ps is the coupled degradation of transmembrane anti-Sigma factors to activate ECF Sigma factor regulons. However, additional signaling mechanisms continue to emerge as more prokaryotic S2Ps are characterized, including direct proteolysis of membrane embedded transcription factors and proteolysis of non-transcriptional membrane proteins or membrane protein remnants. In this review we seek to comprehensively review the functions of S2Ps in bacteria and bacterial pathogens and attempt to organize these proteases into conceptual groups that will spur further study.

Intramembrane proteases as drug targets

“…Bacterial S2Ps are involved in cleavage of transcriptional regulators, mainly transmembrane-tethered antisigma factors, which after cleavage activate sigma factor regulons (reviewed by Schneider et al [15]). In the pathogen Mycobacterium tuberculosis, three putative S2Ps exist: Rip1, 2, and 3.…”

Involvement of a conserved GFG motif region in substrate binding by RseP, an Escherichia coliS2P protease

“…I-CLiPs are found in all kingdoms of life and can be classified into several families, based on amino acid sequence homology and the residues involved in catalysis, including S2P proteases (zinc metalloproteinases), rhomboid proteases (serine proteases) and g-secretase/signal peptide peptidases (aspartyl proteases) (Ha, 2009;Wolfe, 2009;Urban, 2013). Recent research revealed that these I-CLiPs play important roles in a variety of biological processes, including lipid homeostasis, EGF signaling, Notch signaling, stress response and bacterial sporulation and virulence (Nakayama et al, 2011;Kroos and Akiyama, 2013;Rawson, 2013;Schneider and Glickman, 2013;Lastun et al, 2016). I-CLiPs have been associated with several diseases such as Alzheimer's disease and Parkinson's disease (Walder et al, 2005;De Strooper et al, 2012;Song et al, 2015;Spinazzi and De Strooper, 2016).…”

Arabidopsis thaliana intramembrane proteases

“…RIP is performed by intramembrane proteases-an integral membrane proteins able to hydrolyze a transmembrane helix of their substrates and release them from the membrane. This relatively recently discovered class of proteases occurs ubiquitously in all living organisms from bacteria through archaea to eukarya (Adam 2013;Schneider and Glickman 2013;Knopf et al 2012). The first described intramembrane protease was site-2 protease (S2P), identified in human cells in 1997 (Rawson et al 1997).…”