Taking control: Hijacking of Rab GTPases by intracellular bacterial pathogens

Abstract

Intracellular bacterial pathogens survive and replicate within specialized eukaryotic cell organelles. To establish their intracellular niches these pathogens have adopted sophisticated strategies to control intracellular membrane trafficking. Since Rab-family GTPases are critical regulators of endocytic and secretory membrane trafficking events, many intracellular pathogens have evolved specific mechanisms to modulate or hijack Rab GTPases dynamics and trafficking functions. One such strategy is the delivery of bacterial effectors through specialized machines to specifically target Rab GTPases. Some of these effectors functionally mimic host proteins that regulate the Rab GTP cycle, while others regulate Rabs proteins through their post-translation modifications or proteolysis. In this review, we examine how the localization and function of Rab-family GTPases are altered during infection with 3 well-studied intracellular bacterial pathogens, Mycobacterium tuberculosis, Salmonella enterica and Legionella pneumophila. We also discuss recent findings about specific mechanisms by which these intracellular pathogens target this protein family.

Keywords: Legionella pneumophila; Mycobacterium tuberculosis; Rab GTPases; Salmonella enterica; intracellular membrane trafficking; intracellular pathogens.

Figure 1.

Trafficking model of the Mycobacterium-containing vacuole. After phagocytosis the Mycobacterium-containing vacuole acquires early-phagocytic features and Rab GTPases (green circles). However, it does not interact with the late endocytic pathway and does not acquire lysosomal markers, such as lysosomal hydrolases, the vATPase and lysosomal glycoproteins.

Figure 2.

Trafficking model of the Salmonella-containing vacuole. (A) After phagocytosis the Salmonella-containing vacuole (SCV) acquires first early-endocytic features and later most of the lysosomal features. It also acquires sequentially early endocytic Rab GTPases and Rab7 (green circles). However, lysosomal hydrolases are not delivered to the SCV due to a SifA-mediated block of Rab9- and MPR-dependent transport pathway. Broad-host range Salmonella serovars, such as S. Typhimurium, target Rab32 and related Rab GTPases through GtgE and SopD2 and consequently inhibit the delivery of lysosome-related organelle (LRO) enzymes and antimicrobial factors to the LRO and SCV. (B) In contrast to the majority of other Salmonella serovars, the human-adapted S. Typhi does not deliver GtgE and SopD2 and, consequently, succumbs to the Rab32-dependent antimicrobial pathway in mice.

Figure 3.

Trafficking model of the Legionella-containing vacuole. After phagocytosis the Legionella-containing vacuole (LCV) does not interact with the endocytic pathway and does not acquire any of endocytic Rab GTPases (green circles). However, it acquires the secretory Rab, Rab1, which is regulated and post-translationally modified by the Legionella T4SS effectors, DrrA, AnkX, SidD, Lem3, LepB and SidE.