Activation of the extracytoplasmic function σ factor σ^V by lysozyme

Abstract

σ V is an extracytoplasmic function (ECF) σ factor that is found exclusively in Firmicutes including Bacillus subtilis and the opportunistic pathogens Clostridioides difficile and Enterococcus faecalis. σ V is activated by lysozyme and is required for lysozyme resistance. The activity of σ V is normally inhibited by the anti-σ factor RsiV, a transmembrane protein. RsiV acts as a receptor for lysozyme. The binding of lysozyme to RsiV triggers a signal transduction cascade which results in degradation of RsiV and activation of σ V . Like the anti-σ factors for several other ECF σ factors, RsiV is degraded by a multistep proteolytic cascade that is regulated at the step of site-1 cleavage. Unlike other anti-σ factors, site-1 cleavage of RsiV is not dependent upon a site-1 protease whose activity is regulated. Instead constitutively active signal peptidase cleaves RsiV at site-1 in a lysozyme-dependent manner. The activation of σ V leads to the transcription of genes, which encode proteins required for lysozyme resistance. Extracytoplasmic function (ECF) σ factor backgroundECF σ factors belong to the σ 70 family of σ factors and contain only the σ 2 and σ 4.2 domains. These are homologous to the σ 70 σ 2 and σ 4.2 domains and are required for binding to the -35 and -10 regions of target promoters (Helmann, 2002;2016;Staroń et al., 2009). In addition, most ECF σ factors are required for their own expression. The activity of most ECF σ factors is inhibited by a cognate anti-σ factor which is often encoded within the σ factor operon. Many but not all anti-σ factors are membrane proteins (Staroń et al., 2009). The σ factor activity is induced by inhibiting the function of the anti-σ factor. Activation of the σ factor can occur by one of several mechanisms; a conformational change in the anti-σ factor releases the σ factor, an anti-anti-σ factor binds to the anti-σ factor inducing σ factor release, or destruction of the anti-σ factor via regulated intramembrane proteolysis (Ho and Ellermeier, 2012;Helmann, 2016). Here, we will focus on activation of ECF σ factors by degradation of the anti-σ factor. In the presence of an inducing signal, a site-1 protease cleaves the extracellular domain of an anti-σ factor. Following site-1 protease cleavage, the truncated anti-σ factor is cleaved by a site-2 protease within the transmembrane region of the anti-σ factor. The remainder of the anti-σ factor is then degraded by cytosolic proteases. This frees the σ factor to interact with RNA polymerase and transcribe target genes (Brown et al., 2000;Ho and Ellermeier, 2012;Helmann, 2016).The ECF σ factor σ V is found exclusively in Firmicutes or low GC Gram-positive bacteria and belongs to the ECF30 family of ECF σ factors (Staroń et al., 2009). The σ V system is encoded by the model organism Bacillus subtilis, as well as the opportunistic pathogens Enterococcus faecalis and Clostridioides difficile (Fig. 1). σ V is not present in all Firmicutes or even closely related species. While present in B. subtilis, σ V is not present in B. anthrac...

Tunable phenotypic variability through an autoregulatory alternative sigma factor circuit

“…Additionally, an alternative sigma factor plays a role in generating phenotypic diversity in Mycobacteria (Ghosh et al 2011;Sureka et al 2008) . Two other obvious candidates for further study are the pathogens Enterococcus faecalis and Clostridioides difficile (Ho and Ellermeier 2019) , which also have a σ V pathway that is responsive to lysozyme.…”

Role of Regulated Proteolysis in the Communication of Bacteria With the Environment

“…The activity of signal peptidases is not regulated but constitutive, and RsiV cleavage in absence of lysozyme is prevented by two amphipathic helices that occlude the cleavage site (Lewerke et al, 2018). It has been hypothesized that binding of lysozyme to RsiV pulls the amphipathic helix into a β−sheet conformation, which exposes the cleavage site for the signal peptidases (Ho and Ellermeier, 2019). The site-2 cleavage of RsiV is performed by RasP, a membrane-embedded metalloprotease homologous to E. coli RseP (Figures 4A,B).…”

“…RasP cleaves within the transmembrane domain of RsiV releasing the RsiV N-terminal cytosolic domain bound to the σ SigV factor into the cytosol. Similarly to RseA and MucA (Figure 4A), it is assumed that the N-domain of RsiV is degraded by cytosolic proteases although they have not been identified yet (Ho and Ellermeier, 2019).…”

ECF σ factors with regulatory extensions: the one‐component systems of the σ universe

“…In the case of prototypical ECFs, the interaction between the two proteins is mediated by specific binding of the ECF by the anti‐σ domain of the anti‐σ factor (see reviews by Donohue, ; Ho and Ellermeier, ; Park and Roe, in this issue for examples) (Fig. C).…”