Multiple Roles of the Cytoskeleton in Bacterial Autophagy
Figure 2
Current understanding of the roles of the cytoskeleton in autophagy.
A. Models for the role of actin in autophagy. (I) ATG9 is a transmembrane protein that delivers membrane to growing phagophores. ARP2/3 is a highly conserved seven-subunit protein complex used to nucleate actin filaments and organize them into branched arrays. The polymerization of actin enables the movement of ATG9 to the phagophore assembly site (PAS). (II) In the case of ubiquitin (Ub)-mediated selective autophagy, actin can promote the fusion of autophagosomes and lysosomes to degrade ubiquitinated substrates. (III) After escaping from the phagosome to the cytosol, some bacterial pathogens initiate actin-based motility; most pathogens studied so far promote actin polymerization by using the ARP2/3 complex. Actin polymerization propels the bacteria through the cytosol and into neighbouring cells, allowing them to avoid autophagy. In the case of Listeria, actin polymerization by ActA also masks the bacteria from autophagic recognition. (IV) In the case of Shigella, actin polymerization by IcsA is strictly required for recognition by ATG5 and bacterial autophagy. When autophagy is induced, PI3P phospholipid associated with phagophores recruits WIPI-2, TECPR1, and ATG5. Damaged mitochondria and protein aggregates can also be recognized by the WIPI-2-TECPR1-ATG5 pathway [16], [17]. B. Models for the role of microtubules in autophagy. (I) Microtubules (MT) and dynein help move autophagosomes from peripheral locations in the cell to the MTOC, where lysosomes are concentrated. ATG8 family proteins could anchor autophagosomes to dynein and transport autophagosomes along the microtubule tracks. ATG8 family proteins could also bind directly to microtubules and by increasing the affinity between microtubules and autophagosomes may facilitate autophagosome trafficking. (II) Following entry into host cells, Salmonella are inside a spacious phagosome until the phagosome fuses with lysosomes and shrinks around the bacterium; this compartment is called the SCV. SifA is important for Salmonella-induced filament (Sif) formation along microtubules and regulates microtubule-motor (e.g., dynein and kinesin) accumulation on the Sif and the SCV. This regulation may also impact the trafficking of autophagosomes. C. Models for the role of intermediate filaments in autophagy. (I) The phosphorylation of Beclin 1 by the protein kinase Akt promotes a Beclin 1/14-3-3/vimentin complex and inhibits the role of Beclin 1 in autophagy. 14-3-3 proteins are a family of conserved adaptor and scaffolding proteins. (II) Following internalization, Chlamydia remodel intermediate filaments (IFs) to form an inclusion and maintain a replicative niche. 14-3-3β localizes in the inclusion membrane. The autophagy machinery is recruited to the inclusion in a cytoskeleton-dependent manner, but the precise role of autophagy in formation and maintenance of the chlamydial inclusion and in bacterial survival is unknown. D. Models for the role of septins in autophagy. (I) Septins may control autophagosome size and shape and also function as cytoskeleton scaffolds on autophagic membranes. Septin filaments are required for efficient recruitment of autophagy critical components including p62 and ATG8 family proteins. (II) When devoid of actin tails, cytosolic bacteria, including Shigella and M. marinum, can be trapped in septin cages and targeted to autophagy. Septins have been shown to scaffold the autophagy machinery around actin-polymerizing bacteria.