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Bacterial actin MreB in cell morphogenesis

Reference	BB/F001924/1
Principal Investigator / Supervisor	Professor Kenn Gerdes
Co-Investigators / Co-Supervisors
Institution	Newcastle University
Department	Inst for Cell and Molecular Biosciences
Funding type	Research
Value (£)	432,556
Status	Completed
Type	Research Grant
Start date	07/01/2008
End date	06/09/2011
Duration	44 months

Abstract

Bacterial cell shape is determined by the main component of the cell wall, the peptidoglycan (PG). How PG synthesis is regulated in time and space is only beginning to be understood. One major breakthrough was the discovery that helical filaments of the actin homolog MreB seem to direct the synthesis of nascent PG and is also required to maintain cell shape, thus linking PG synthesis to cell morphogenesis. The role of MreB in PG synthesis is general since such diverse model organisms as E. coli, B. subtilis and C. crescentus all require functional MreB to maintain cell shape. Recent evidence suggests that the intracellular MreB cables interacts with MreC, a bitopic membrane protein that is also required to maintain cell shape. In turn, MreC interacts with the penicillin-binding proteins, notably PBP2 and PBP3, transpeptidases that are required for lateral and septal cell wall synthesis, respectively. These results suggest that MreB controls extracellular PG synthesis via its interaction with MreC. In C. crescentus, MreB exhibits a dynamic localization pattern with an assembly at mid-cell in predivisional cells depending on FtsZ. PBP2 exhibits a helical pattern along the length of the cells that depends on both MreB and MreC. Moreover, inactivation of MreB leads to assembly of PBP2 at mid-cell, also by a mechanism that depends on FtsZ. Thus, the cell wall synthetic machinery seems to be organized by a complicated interplay between MreB, MreC and FtsZ. In E. coli, FtsZ is required for the switch from lateral to septal PG synthesis and it is therefore possible that PG synthesis is directed by an interplay between MreB and FtsZ also also in this organism. The objective of proposal is to identify novel interaction partners for MreB and MreC that are involved in cell shape determination and/or cell division. Using cytological, genetic and biochemical approaches, we will identify partners for MreB and MreC, and determine the biological function(s) of such interactions.

Summary

Shape is a characteristic of all living cells, including bacteria. Bacteria come in many different shapes, including rods, spheres (cocci), crescents and helices. Many pathogenic bacteria, including e.g. Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa are rod-shaped. These bacteria have a cell wall that chemically resembles the stiff exoskeletons of insects and determines the shape of the cells. The chemical components that make up the bacterial cell wall has been elucidated (known as peptidoglycan) but it is not known how the shape of the wall is maintained during cell growth and division. In recent years, however, it has become clear that bacteria contain an intracellular network of actin filaments or cables that control cell shape and also mediate intracellular transport of cellular DNA and proteins. One such essential filament-forming protein is the bacterial actin MreB. It was discovered only recently that MreB forms dynamic filaments that are required to maintain the shape of rod-shaped bacteria. This function appears conserved in evolution since MreB homologs are present in bacteria that diverged more than two billion years ago. In such diverse organisms, MreB interacts with a protein called MreC, a trans-membrane protein that interacts with cell wall synthesizing proteins called penicillin-binding proteins (PBPs). The PBPs synthesize peptidoglycan and are essential to maintain cell wall integrity and cell shape. These consistent observations have led to the general hypothesis that the intracellular actin MreB cables control cell shape by orchestrating the extracellular cell wall synthesizing enzymes, and that the membrane-bound MreCD complex functions as a bridge between MreB and the PBPs. The accomplishment of the research proposed here will yield results that can decide whether this important and general hypothesis is correct. Moreover, it is not yet understood how cell wall synthesis is coordinated with cell division. Several recent observations support that actin MreB might be pivotal in coordinating cell wall growth with cell division. Most importantly, MreB interacts with the major bacterial cell division factor FtsZ, a bacterial tubulin homolog. In bacteria, cell division is initiated by the formation of a ring at mid-cell that consists of FtsZ molecules. The FtsZ ring determines the position where the mother cell divides and recruits all other known cell division factors to the invaginating septum. The recently detected interaction between MreB and FtsZ raises the possibility that these two proteins interact to coordinate cell wall synthesis with cell division. Here, we will further investigate this challenging hypothesis. Since almost all rod-shaped pathogenic bacteria contain MreB and FtsZ, the major findings from this research will be of both general and medical importance.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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