Actin dynamics in host-pathogen interaction

Abstract

The actin cytoskeleton and Rho GTPase signaling to actin assembly are prime targets of bacterial and viral pathogens, simply because actin is involved in all motile and membrane remodeling processes, such as phagocytosis, macropinocytosis, endocytosis, exocytosis, vesicular trafficking and membrane fusion events, motility, and last but not least, autophagy. This article aims at providing an overview of the most prominent pathogen-induced or -hijacked actin structures, and an outlook on how future research might uncover additional, equally sophisticated interactions.

Keywords: actin dynamics; bacterial invasion; host-pathogen interaction; viral entry; virulence factors.

Figure 1

Molecular mechanisms of actin filament assembly and their targeting by virulence factors. Actin filament turnover is tightly regulated by catalytic nanomachines and their cofactors (for details, see text or Ref. 12). Assembly of F‐actin is manipulated at virtually every level by bacterial virulence factors. The columns mark the phases of F‐actin production and the virulence actors (blue) are placed about where they affect filament turnover. The factors depicted are only few examples and the list is far from being complete. Nonetheless, for the future, we expect many more virulence factors and/or mechanisms to be identified that affect these and other steps of dynamic actin turnover such as severing or capping. Note that the molecular mechanisms evolved by bacteria to nucleate/elongate actin are not identical, but at best similar to those of the host cell as drafted in the chart.

Figure 2

Cellular actin assemblies. Gross structure of cell membranes with actin assemblies and the respective Arp2/3‐complex activators (in red) or formins (in blue) that were described to contribute to their formation. The listing cannot be complete and requires continuous revision, as our knowledge on the cellular roles of these actin‐generating nanomachines is continuously growing. Original references for the mentioned actions of NPFs and formins are numerous and can be found in recent competitive reviews [2, 3, 4, 11, 13, 15]. Note that pathogens were found capable to usurp many if not most of these actin assemblies and that the currently unseen ones are expected to be found in the future.

Figure 3

The Rho‐GTPase activation cycle and its manipulation by virulence factors. Rho GTPases cycle between an inactive GDP‐bound state and an active GTP‐bound state. So‐called GEFs regulate their activation, whereas GAPs enhance their intrinsic hydrolase leading to inactivation. In the GTP‐bound state, the GTPase binds to its downstream effectors. Finally, GDIs keep Rho GTPases in an inactive state and protect them from degradation. The small GTPase activation cycle is targeted by bacterial virulence factors at virtually every step. Virulence factors (in blue) are certainly not complete but just exemplary for entire families of factors and the identification of more virulence determinants and mechanisms is expected from future research. Targeting of these processes with small molecules might pave the way to novel pathoblockers or anticancer drugs.

Figure 4

Virus infections harness actin assembly at membranes at all stages. Schematic representation of cellular locations where virus infection and propagation engages membranes and actin dynamics. The figure focuses on entry (upper side) and egress (right side) and only hints at the multiple possibilities of where virus assembly can take place such as ER and Golgi compartments. Virtually, every type of membrane and actin assembly is utilized by one or the other virus. Hence, it is not surprising that even mitochondria 98 or inhospitable places like peroxisomes can be exploited for virus propagation. Therefore, the figure must remain superficial and just repeats common themes. For instance, the term ‘endocytosis’ stands for all types of endocytosis not only clathrin‐mediated mechanisms.