FtsZ ring stability: of bundles, tubules, crosslinks, and curves

Abstract

The first step in bacterial cytokinesis is the assembly of a stable but dynamic cytokinetic ring made up of the essential tubulin homolog FtsZ at the future site of division. Although FtsZ and its role in cytokinesis have been studied extensively, the precise architecture of the in vivo medial FtsZ ring (Z ring) is not well understood. Recent advances in superresolution imaging suggest that the Z ring comprises short, discontinuous, and loosely bundled FtsZ polymers, some of which are tethered to the membrane. A diverse array of regulatory proteins modulate the assembly, stability, and disassembly of the Z ring via direct interactions with FtsZ. Negative regulators of FtsZ play a critical role in ensuring the accurate positioning of FtsZ at the future site of division and in maintaining Z ring dynamics by controlling FtsZ polymer assembly/disassembly processes. Positive regulators of FtsZ are essential for tethering FtsZ polymers to the membrane and promoting the formation of stabilizing lateral interactions, permitting assembly of a mature Z ring. The past decade has seen the identification of several factors that promote FtsZ assembly, presumably through a variety of distinct molecular mechanisms. While a few of these proteins are broadly conserved, many positive regulators of FtsZ assembly are limited to small groups of closely related organisms, suggesting that FtsZ assembly is differentially modulated across bacterial species. In this review, we focus on the roles of positive regulators in Z ring assembly and in maintaining the integrity of the cytokinetic ring during the early stages of division.

Fig 1

(A) Schematic of FtsZ assembly, maturation, and disassembly, depicted during different stages of the bacterial cell cycle. In a newborn cell, FtsZ is present as unassembled monomers or short oligomers. The chromosome (black curved lines) with a single origin of replication (red oval) is shown. Toward the end of chromosome replication and segregation, FtsZ (blue circles) polymerizes at the future site of division and is tethered to the membrane by specific FtsZ-interacting proteins. During this first step in cytokinesis, early divisomal proteins that directly bind FtsZ and promote lateral associations among FtsZ polymers stabilize the Z ring. During the second step in cytokinesis, maturation of the initial Z ring complex takes place by recruitment of downstream division proteins to the division site. The final step in cytokinesis constitutes the depolymerization and constriction of the Z ring, followed by separation into two daughter cells. (B) Domain organization of FtsZ with interaction sites for species-specific FtsZ regulators affecting the assembly and stability of the nascent Z ring during cytokinesis. The domain structure is not drawn to scale and shows amino acid residue numbers from the E. coli FtsZ sequence. The amino acid residues of the conserved CTT (C-terminal tail) and the CTV (C-terminal variable) regions of FtsZ in the three well-studied species are indicated below. FtsZ regulators conserved in all three species are shown in black, those found in E. coli are shown in red, and those in B. subtilis are shown in green. EzrA, a negative regulator of FtsZ in Bacillus, is included in this diagram because of its potential role in tethering FtsZ to the membrane. The FtsZ interaction sites of ZapB from E. coli and FzlA and FzlC from Caulobacter are currently undetermined.

Fig 2

Diagrammatic representation of proteins that localize at the site of future division in E. coli (A), B. subtilis (B), and Caulobacter (C) and promote the Z ring assembly and stability during the first step in bacterial cytokinesis. Z, FtsZ; E, FtsE; X, FtsX; IM, inner membrane; PG, peptidoglycan; OM, outer membrane. ZapB is oligomeric in solution and has been reported to form a ring-like structure (not shown) with a smaller radius than that of the Z ring in E. coli. EzrA, a negative regulator of FtsZ in Bacillus, is included because of its putative role in tethering FtsZ to the membrane. In Caulobacter, FtsA is a late recruit to the divisome.

Fig 3

Diagram (top) and representative electron micrographs (bottom) of the effects of various positive regulators on the higher-order structures of FtsZ polymers in the Z ring. Blue circles represent FtsZ monomers, and solid green circles or rings represent various FtsZ stabilizers in different species. From left to right: FtsZ in the presence of E. coli ZapA shows cross-linked or bundled polymers, reprinted from reference with permission from the American Chemical Society; FtsZ in the presence of E. coli ZapD shows bundled FtsZ polymers, reprinted from reference with permission; FtsZ in the presence of Bacillus SepF shows FtsZ tubules (horizontal white arrowheads) and SepF rings (vertical white arrowheads), with images courtesy of Leendert Hamoen and reprinted from reference with permission from Nature Publishing Group; and FtsZ in the presence of Caulobacter FzlA shows curved FtsZ polymers (white arrows), reprinted from reference with permission from Elsevier. Note that ZapD-mediated FtsZ bundles are shown as a representative image of FtsZ polymer bundling by various FtsZ regulators. Scale bars from left to right: 100 nm, 200 nm, 50 nm, and 100 nm.