Control of the <i>Pseudomonas aeruginosa</i> LbcA•CtpA proteolytic complex and its substrates

<i>Pseudomonas aeruginosa</i> is a highly adaptable bacterial pathogen with a resilient cell envelope. This envelope must be elongated as cells grow, which requires coordinated biosynthesis of the inner and outer membranes and the peptidoglycan cell wall. Cell wall endopeptidases are essential to expand the peptidoglycan sacculus, and the LbcA•CtpA proteolytic complex controls the activity of multiple endopeptidases by degrading them. Here, we report an investigation into control of the LbcA•CtpA proteolytic complex and its substrates. LbcA and CtpA levels were unaffected by growth rate, which corresponded with constitutive expression of their genes. For CtpA, this was explained by its arrangement in a complex operon containing an internal <i>ctpA</i> promoter. Despite constitutive LbcA and CtpA production, the LbcA•CtpA substrate levels were higher when cells were growing rapidly. In most cases, this correlated with modestly higher substrate gene expression in the exponential phase. However, most of the control came from reduced CtpA activity when cells were growing rapidly. Our data suggest that CtpA activity might be affected by phospholipid transport and related processes in the cell envelope. A similar phenomenon was reported to affect the <i>Escherichia coli</i> NlpI•Prc complex, even though there are major sequence and structural differences between the NlpI•Prc and LbcA•CtpA complexes. This makes it likely that growth-rate-dependent autolysin control by these proteolytic complexes is widely conserved, even if they are composed of non-orthologous proteins in some cases.IMPORTANCECarboxyl-terminal processing proteases occur in all domains of life. Some are associated with bacterial virulence, including <i>P. aeruginosa</i> CtpA, which works with the outer membrane lipoprotein LbcA to degrade cell wall endopeptidases. We report that the LbcA•CtpA complex activity is coordinated with growth rate, ensuring appropriate levels of its substrates for cell wall expansion. The mechanism appears to be connected to phospholipid transport, much like a phenomenon reported for <i>Escherichia coli</i> NlpI•Prc complex. However, the NlpI•Prc and LbcA•CtpA complexes are not orthologs. Therefore, growth-rate-dependent control by analogous but dissimilar complexes might be a widely conserved mechanism, and one that could perhaps be targeted for therapeutic intervention.