Ancestral homologues of the major eukaryotic cytoskeletal families, tubulin and actin, play critical roles in cytokinesis of bacterial cells. FtsZ is the ancestral homologue of tubulin and assembles into the Z ring that determines the division plane. FtsA is an ancestral homologue of actin and is involved in coordinating cell wall synthesis during cytokinesis. FtsA assists in the formation of the Z ring and also has a critical role in recruiting downstream division proteins to the Z ring to generate the divisome that divides the cell. Spatial regulation of cytokinesis occurs at the stage of Z ring assembly and regulation of cell size occurs at this stage or during Z ring maturation.

Bacterial cell division is driven by the divisome, a ring-shaped protein complex organized by the bacterial tubulin homolog FtsZ. Although most of the division proteins in Escherichia coli have been identified, how they assemble into the divisome and synthesize the septum remains poorly understood. Recent studies suggest that the bacterial actin homolog FtsA plays a critical role in divisome assembly and acts synergistically with the FtsQLB complex to regulate the activity of the divisome. FtsEX, an ATP-binding cassette transporter-like complex, is also necessary for divisome assembly and inhibits division when its ATPase activity is inactivated. However, its role in division is not clear. Here, we find that FtsEX acts on FtsA to regulate both divisome assembly and activity. FtsX interacts with FtsA and this interaction is required for divisome assembly and inhibition of divisome function by ATPase mutants of FtsEX. Our results suggest that FtsEX antagonizes FtsA polymerization to promote divisome assembly and the ATPase mutants of FtsEX block divisome activity by locking FtsA in the inactive form or preventing FtsA from communicating with other divisome proteins. Because FtsEX is known to govern cell wall hydrolysis at the septum, our findings indicate that FtsEX acts on FtsA to promote divisome assembly and to coordinate cell wall synthesis and hydrolysis at the septum. Furthermore, our study provides evidence that FtsA mutants impaired for self-interaction are favored for division, and FtsW plays a critical role in divisome activation in addition to the FtsQLB complex.

Cell division in Escherichia coli is mediated by a large protein complex called the divisome. Most of the divisome proteins have been identified, but how they assemble onto the Z ring scaffold to form the divisome and work together to synthesize the septum is not well understood. In this review, we summarize the latest findings on divisome assembly and activation as well as provide our perspective on how these two processes might be regulated.

Summary Assembly of the divisome in E. coli occurs in two temporally distinct steps. First, FtsZ filaments attached to the membrane through interaction with FtsA and ZipA coalesce into a Z ring at midcell. After a delay, additional proteins are recruited to the Z ring in a hierarchical manner to form a complete divisome, activated by the arrival of FtsN. Recently, we proposed the interaction of FtsA with itself competes with its ability to recruit downstream division proteins (both require the same IC domain of FtsA) and that ZipA’s essential function is to promote the formation of FtsA monomers. Here, we tested whether overexpression of a downstream division protein could make ZipA dispensable, presumably by shifting the FtsA equilibrium to monomers. Only overexpression of FtsN bypassed ZipA and we identified a motif in the cytoplasmic domain of FtsN required for both the bypass of ZipA and interaction with FtsA. In addition, this cytoplasmic motif has to be linked to the periplasmic E domain of FtsN in order to bypass ZipA, suggesting that FtsN was linking FtsA to periplasmic components of the divisome. These results are used to further elaborate our model for the role of FtsA in recruiting downstream division proteins.

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