Abstract
Peptidoglycan (PG) is the main component of bacterial cell walls and the target for many antibiotics. PG biosynthesis is tightly coordinated with cell wall growth and turnover, and many of these control activities depend upon PASTA-domain containing eukaryotic-like serine/threonine protein kinases (PASTA-eSTK) that sense PG fragments. However, only a few PG biosynthetic enzymes are direct kinase substrates. Here, we identify the conserved ReoM protein as a novel PASTA-eSTK substrate in the Gram-positive pathogen Listeria monocytogenes. Our data show that the phosphorylation of ReoM is essential as it controls ClpCP-dependent proteolytic degradation of the essential enzyme MurA, which catalyses the first committed step in PG biosynthesis. We also identify ReoY as a second novel factor required for degradation of ClpCP substrates. Collectively, our data imply that the first committed step of PG biosynthesis is activated through control of ClpCP protease activity in response to signals of PG homeostasis imbalance.
Highlights
The cell wall of Gram-positive bacteria is a complicated three-dimensional structure that engulfs the cell as a closed sacculus
With ReoM we have identified a missing link in a regulatory pathway that enables Firmicute bacteria to respond to PG biosynthesis fluctuations associated with growth and division
In L. monocytogenes, the sensory module of this pathway comprises the membrane integral protein kinase PrkA and the cognate protein phosphatase PrpC, their newly discovered substrate ReoM and the associated factors ReoY and MurZ, which together regulate ClpCP activity, the effector protease that acts on MurA (Figure 9)
Summary
The cell wall of Gram-positive bacteria is a complicated three-dimensional structure that engulfs the cell as a closed sacculus. The main component of bacterial cell walls is peptidoglycan (PG), a network of glycan strands crosslinked together by short peptides (Vollmer et al, 2008a). PG biosynthesis starts with the conversion of UDP-GlcNAc into lipid II, a disaccharide pentapeptide that is ligated to a membrane-embedded bactoprenol carrier lipid (Typas et al, 2012). This monomeric PG precursor is flipped from the inner to the outer leaflet of the cytoplasmic membrane by MurJ- and Amjlike enzymes called flippases (Ruiz, 2008; Sham et al, 2014; Meeske et al, 2015). A suite of regulators ensure that spatiotemporal control of PG synthesis is balanced against PG hydrolysis in cycles of bacterial growth and division (Booth and Lewis, 2019)
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