Spatial guidance of cell asymmetry: septin GTPases show the way

Abstract

Eukaryotic cells develop asymmetric shapes suited for specific physiological functions. Morphogenesis of polarized domains and structures requires the amplification of molecular asymmetries by scaffold proteins and regulatory feedback loops. Small monomeric GTPases signal polarity, but how their downstream effectors and targets are spatially co-ordinated to break cell symmetry is poorly understood. Septins comprise a novel family of GTPases that polymerize into non-polar filamentous structures which scaffold and restrict protein localization. Recent studies show that septins demarcate distinct plasma membrane domains and cytoskeletal tracks, enabling the formation of intracellular asymmetries. Here, we review these findings and discuss emerging mechanisms by which septins promote cell asymmetry in fungi and animals.

Figure 1. The Septin GTPase Module

A) Based on sequence similarity, fourteen human septins (SEPT1–14) are classified into four groups: SEPT2, SEPT3, SEPT6 and SEPT7. Septins of the SEPT7 group have also been classified under the SEPT2 group (104). Typical septins consist of three conserved domains: a phosphoinositide-binding polybasic (PB) region, a GTP binding and/or hydrolysis domain (GTPase) and the septin unique element (SUE). Septins of the SEPT6 group lack GTPase activity owing to a mutation (T78*) in the switch I region, which interacts with the γ-phosphate of GTP (22). Septins vary in the length and sequence of their C-terminal tails, which contain coiled-coil (CC) motifs. A few septins (e.g., SEPT9, SEPT8) contain long N-terminal extensions with proline rich domains. B) Through their nucleotide-bound GTPase and SUE domains, septin monomers associate with one another to form larger hetero-oligomeric complexes (7). Septin oligomerization is aided by the TRiC/CCT chaperone (105) and takes place in a combinatorial fashion; septins of a particular group associate with septins from another group in a specific order (6, 106). Septin hetero-oligomers polymerize into non-polar filaments, which in turn pair up to form higher order structures that serve as protein scaffolds and diffusion barriers. While monomeric septins are thought to be biologically inactive (red), higher order septin filaments represent the biologically active (green) form of septin GTPases (11). Post-translational modifications (PTMs) and Rho signaling control the assembly and turnover of septin oligomers (4). Schematic was adopted with modifications from (11) and (4).

Figure 2. Septins affect asymmetry in the membrane

Schematic of three ways by which septin filaments could affect the organization and shape of biological membranes: 1) septins block the lateral diffusion of membrane proteins, barricading proteins within a distinct region (light salmon color) of the lipid bilayer (sandy brown); 2) membrane regions cave in under a rigid meshwork of bent septin filaments, which deform the cell membrane; 3) septin-bound regions of the membrane bilayer are rigidified, limiting protrusive activity to more elastic areas of the membrane.

Figure 3. Septins demarcate distinct F-actin and microtubule tracks

A) Septin (green) association with F-actin (orange) in mammalian cells that exhibit mesenchymal (left) and amoeboid (right) types of motility. Septin interaction with the actomyosin network at distinct intracellular regions might be critical for cellular mechanotransduction and directional cell motility. B) Septin (green) association with distinct microtubule tracks (red) in polarizing (left) and polarized (right) epithelia. Septins associate with perinuclear microtubule bundles and provide guidance cues for the positioning of the microtubule network and possibly for the directional transport of membrane vesicles and organelles.