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The Staphylococcus aureus cell division protein, DivIC, interacts with the cell wall and controls its biosynthesis.

ABSTRACT: Bacterial cell division is a complex, dynamic process that requires multiple protein components to orchestrate its progression. Many division proteins are highly conserved across bacterial species alluding to a common, basic mechanism. Central to division is a transmembrane trimeric complex involving DivIB, DivIC and FtsL in Gram-positives. Here, we show a distinct, essential role for DivIC in division and survival of Staphylococcus aureus. DivIC spatially regulates peptidoglycan synthesis, and consequently cell wall architecture, by influencing the recruitment to the division septum of the major peptidoglycan synthetases PBP2 and FtsW. Both the function of DivIC and its recruitment to the division site depend on its extracellular domain, which interacts with the cell wall via binding to wall teichoic acids. DivIC facilitates the spatial and temporal coordination of peptidoglycan synthesis with the developing architecture of the septum during cell division. A better understanding of the cell division mechanisms in S. aureus and other pathogenic microorganisms can provide possibilities for the development of new, more effective treatments for bacterial infections.

SUBMITTER: Tinajero-Trejo M

PROVIDER: S-EPMC9652317 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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The Staphylococcus aureus cell division protein, DivIC, interacts with the cell wall and controls its biosynthesis.

Tinajero-Trejo Mariana M Carnell Oliver O Kabli Azhar F AF Pasquina-Lemonche Laia L Lafage Lucia L Han Aidong A Hobbs Jamie K JK Foster Simon J SJ

Communications biology 20221111 1

Bacterial cell division is a complex, dynamic process that requires multiple protein components to orchestrate its progression. Many division proteins are highly conserved across bacterial species alluding to a common, basic mechanism. Central to division is a transmembrane trimeric complex involving DivIB, DivIC and FtsL in Gram-positives. Here, we show a distinct, essential role for DivIC in division and survival of Staphylococcus aureus. DivIC spatially regulates peptidoglycan synthesis, and ...[more]

PMID: 36369270

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Project description:Phages and bacteria have a long history of co-evolution. However, these dynamics of phage-host interactions are still largely unknown; identification of phage inhibitors that remodel host metabolism will provide valuable information for target development for antimicrobials. Here, we perform a comprehensive screen for early-gene products of ΦNM1 that inhibit cell growth in Staphylococcus aureus. A small membrane protein, Gp11, with inhibitory effects on S. aureus cell division was identified. A bacterial two-hybrid library containing 345 essential S. aureus genes was constructed to screen for targets of Gp11, and Gp11 was found to interact with MurG and DivIC. Defects in cell growth and division caused by Gp11 were dependent on MurG and DivIC, which was further confirmed using CRISPRi hypersensitivity assay. Gp11 interacts with MurG, the protein essential for cell wall formation, by inhibiting the production of lipid II to regulate peptidoglycan (PG) biosynthesis on the cell membrane. Gp11 also interacts with cell division protein DivIC, an essential part of the division machinery necessary for septal cell wall assembly, to disrupt the recruitment of division protein FtsW. Mutations in Gp11 result in loss of its ability to cause growth defects, whereas infection with phage in which the gp11 gene has been deleted showed a significant increase in lipid II production in S. aureus. Together, our findings reveal that a phage early-gene product interacts with essential host proteins to disrupt PG biosynthesis and block S. aureus cell division, suggesting a potential pathway for the development of therapeutic approaches to treat pathogenic bacterial infections.ImportanceUnderstanding the interplay between phages and their hosts is important for the development of novel therapies against pathogenic bacteria. Although phages have been used to control methicillin-resistant Staphylococcus aureus infections, our knowledge related to the processes in the early stages of phage infection is still limited. Owing to the fact that most of the phage early proteins have been classified as hypothetical proteins with uncertain functions, we screened phage early-gene products that inhibit cell growth in S. aureus, and one protein, Gp11, selectively targets essential host genes to block the synthesis of the peptidoglycan component lipid II, ultimately leading to cell growth arrest in S. aureus. Our study provides a novel insight into the strategy by which Gp11 blocks essential host cellular metabolism to influence phage-host interaction. Importantly, dissecting the interactions between phages and host cells will contribute to the development of new and effective therapies to treat bacterial infections.

Project description:Bacterial cell division is a complex and highly regulated process requiring the coordination of many different proteins. Despite substantial work in model organisms, our understanding of the systems regulating cell division in noncanonical organisms, including critical human pathogens, is far from complete. One such organism is Staphylococcus aureus, a spherical bacterium that lacks known cell division regulatory proteins. Recent studies on GpsB, a protein conserved within the Firmicutes phylum, have provided insight into cell division regulation in S. aureus and other related organisms. It has been revealed that GpsB coordinates cell division and cell wall synthesis in multiple species. In S. aureus, we have previously shown that GpsB directly regulates FtsZ polymerization. In this study, using Bacillus subtilis as a tool, we isolated spontaneous suppressors that abrogate the lethality of S. aureus GpsB overproduction in B. subtilis. Through characterization, we identified several residues important for the function of GpsB. Furthermore, we discovered an additional role for GpsB in wall teichoic acid (WTA) biosynthesis in S. aureus. Specifically, we show that GpsB directly interacts with the WTA export protein TarG. We also identified a region in GpsB that is crucial for this interaction. Analysis of TarG localization in S. aureus suggests that WTA machinery is part of the divisome complex. Taken together, this research illustrates how GpsB performs an essential function in S. aureus by directly linking the tightly regulated cell cycle processes of cell division and WTA-mediated cell surface decoration. IMPORTANCE Cytokinesis in bacteria involves an intricate orchestration of several key cell division proteins and other factors involved in building a robust cell envelope. Presence of teichoic acids is a signature characteristic of the Gram-positive cell wall. By characterizing the role of Staphylococcus aureus GpsB, an essential cell division protein in this organism, we have uncovered an additional role for GpsB in wall teichoic acid (WTA) biosynthesis. We show that GpsB directly interacts with TarG of the WTA export complex. We also show that this function of GpsB may be conserved in other GpsB homologs as GpsB and the WTA exporter complex follow similar localization patterns. It has been suggested that WTA acts as a molecular signal to control the activity of autolytic enzymes, especially during the separation of conjoined daughter cells. Thus, our results reveal that GpsB, in addition to playing a role in cell division, may also help coordinate WTA biogenesis.

Dataset Information

The Staphylococcus aureus cell division protein, DivIC, interacts with the cell wall and controls its biosynthesis.

Publications

The Staphylococcus aureus cell division protein, DivIC, interacts with the cell wall and controls its biosynthesis.

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