Multiple roles of the cytoskeleton in bacterial autophagy.

Abstract

Several bacterial pathogens are targeted by macroautophagy (referred to as autophagy hereafter), and autophagy is widely recognized as an important antibacterial defence mechanism [1]. On the other hand, new work has shown that some bacterial pathogens have mechanisms to avoid or exploit the autophagy machinery for intracellular survival [2]–[4]. Strikingly, the host cytoskeleton plays a crucial role in autophagy and its ability to restrict or promote bacterial replication. A complete understanding of autophagy-cytoskeleton interactions is therefore needed to enable the manipulation of autophagy for therapeutic purposes. Actin, microtubules, intermediate filaments, and septins are four main cytoskeletal components of vertebrate cells (Box 1), yet their roles in autophagy are not fully understood. This Pearl revisits our current understanding of autophagy-cytoskeleton interactions and highlights new concepts and emerging roles for the cytoskeleton in bacterial autophagy. Box 1. The Four Cytoskeleton Components A. Actin is a globular, multifunctional protein that forms filaments (Figure 3A). Actin (∼40 kDa) is called globular actin (G-actin) in its monomeric form. To generate filamentous actin (F-actin), chains of actin are polymerized (dependent upon adenosine triphosphate [ATP] hydrolysis) and intertwined in a helix with a diameter of ∼7 nm. Actin filaments are polar, with a plus end (where monomers preferentially assemble) and a minus end (where monomers preferentially disassemble). Figure 3 Schematic overview of the four cytoskeleton components. B. Microtubules are highly dynamic, tubular polymers found throughout the cytoplasm (Figure 3B). Microtubules are made from 13 parallel protofilaments composed of α-tubulin and β-tubulin heterodimers (tubulin monomers are ∼50 kDa). The αβ-tubulin dimers assemble in a head-to-tail manner producing microtubule polymers with a diameter of ∼25 nm. Microtubules are polar and by a process called “dynamic instability” (driven by guanosine triphosphate [GTP] hydrolysis) can assemble and disassemble at the plus end. C. Intermediate filaments, a family of proteins encoded by ∼70 genes, are a major structural element of human cells (Figure 3C). Intermediate filament proteins assemble to form a tetrameric subunit, and eight tetrameric subunits associate laterally to form a unit length filament (ULF). Individual ULFs join end to end to form short filaments, and short filaments longitudinally anneal to other ULFs and filaments to form longer filaments. Intermediate filaments have a diameter of ∼11 nm (in between that of actin and microtubules), do not require nucleotide (ATP or GTP) hydrolysis, and are nonpolar because of the antiparallel orientation of tetramers. D. Septins, a fourth component of the cytoskeleton, are evolutionarily conserved GTP-binding proteins that associate with cellular membranes, actin filaments, and microtubules (Figure 3D). Septin subunits (30–65 kDa) are classified into different homology groups and interact through their GTP-binding domain (called the G interface) and their amino-terminal and carboxy-terminal regions (called the NC interface). Septins from different groups (shown in Figure 3D as different shades of red) form complexes (that form rods of 32–40 nm in length) that assemble end to end into nonpolar filaments. Septin filaments can associate laterally and form bundles, and bundles of septin filaments can form higher-order structures, such as rings (which are ∼0.6 µm in diameter).