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Review
. 2016 Mar 8;5(1):11.
doi: 10.3390/cells5010011.

Rab GTPases and the Autophagy Pathway: Bacterial Targets for a Suitable Biogenesis and Trafficking of Their Own Vacuoles

María Milagros López de Armentia  1 , Celina Amaya  2 , María Isabel Colombo  3
Affiliations
Review

Rab GTPases and the Autophagy Pathway: Bacterial Targets for a Suitable Biogenesis and Trafficking of Their Own Vacuoles

María Milagros López de Armentia et al. Cells. .

Abstract

Autophagy is an intracellular process that comprises degradation of damaged organelles, protein aggregates and intracellular pathogens, having an important role in controlling the fate of invading microorganisms. Intracellular pathogens are internalized by professional and non-professional phagocytes, localizing in compartments called phagosomes. To degrade the internalized microorganism, the microbial phagosome matures by fusion events with early and late endosomal compartments and lysosomes, a process that is regulated by Rab GTPases. Interestingly, in order to survive and replicate in the phagosome, some pathogens employ different strategies to manipulate vesicular traffic, inhibiting phagolysosomal biogenesis (e.g., Staphylococcus aureus and Mycobacterium tuberculosis) or surviving in acidic compartments and forming replicative vacuoles (e.g., Coxiella burnetti and Legionella pneumophila). The bacteria described in this review often use secretion systems to control the host's response and thus disseminate. To date, eight types of secretion systems (Type I to Type VIII) are known. Some of these systems are used by bacteria to translocate pathogenic proteins into the host cell and regulate replicative vacuole formation, apoptosis, cytokine responses, and autophagy. Herein, we have focused on how bacteria manipulate small Rab GTPases to control many of these processes. The growing knowledge in this field may facilitate the development of new treatments or contribute to the prevention of these types of bacterial infections.

Keywords: Rab GTPases; autophagy; bacterial pathogens; intracellular bacteria.

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Figures

Figure 1
Figure 1
Rab GTPases and vesicular trafficking modulation by Mycobacterium tuberculosis and Staphylococcus aureus. (A) M. tuberculosis initially resides in a phagosome characterized by the presence of Rab5, Rab10, Rab22b and Rab23 that matures to a late compartment. Approximately 1 h p.i. Mtb secretes ESAT-6, a pore forming toxin, and lyses the membrane promoting p62 and NDP52 anchorage. Together, these proteins stimulate the autophagic pathway, and the damage phagosome is entrapped by an autophagosome. Rab5 remains in the phagosome, inhibiting the proper maturation of the compartment and as a consequence, it inhibits the lysosomal fusion. Finally, Mtb replicates inside the mycobacterial-containing phagosome (MCP). (B) S. aureus transits through an early phagosome with Rab5 and Rab22b that quickly maturates (15 min p.i.) to a late compartment marked by Rab7 and LAMP-1. Alpha hemolysin (Hla) is secreted by the bacteria and causes membrane damage. Autophagy is stimulated by the toxin and autophagosomes are recruited to the damage phagosome. Sa replicates inside the autophagosomes that does not mature to autophagolysosome due to the inhibition of lysosomal fusion. Then, phenol soluble modulin alpha (PMSα) mediates Sa escape to the cytoplasm, where bacteria continue replicating.
Figure 2
Figure 2
Intracellular trafficking route of Coxiella and Legionella. (A) Coxiella initially resides in a parasitophorous vacuole (PV) that takes hours to days to mature into a compartment resembling a lysosome. Rab5 and Rab7 have been shown to be sequentially present on the PV, with Rab5 showing maximal recruitment approximately 20 min p.i. before being replaced by Rab7 which remains on the PV throughout the infection. Between 6 and 12 h post- infection, the PV acquires autophagy markers including LC3 and Rab24. Then, p62 colocalizes with LC3 on PV membranes containing ubiquitinated proteins without affecting the bacterial replication. In addition, Rab1b labels the PV membrane at later p.i. times (6 h). (B) Legionella actively evades endocytic trafficking and creates an ER-derived niche. Effector proteins such as DrrA/SidM, LidA, and RalF, secreted by the T4SS, prolong the association with the ER and inhibit the immediate delivery to lysosomes. Likewise, RavZ cleaves the membrane-conjugated LC3 from pre-autophagosomal structures to persist in immature autophagosomal vacuoles for a period of time that is suitable to differentiate into an acid-resistant replicative form. Then, the subsequent secretion of the effector LepB releases the block to autophagosome maturation, and the adapted progeny continues to replicate within autophagolysosomes.
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