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  • Review Article
  • Published:

Manipulation of host membranes by bacterial effectors

Nature Reviews Microbiology volume 9, pages 635–646 (2011)Cite this article

Subjects

Key Points

  • On infection, bacterial pathogens interact with host membranes to trigger various cellular processes through different mechanisms. These processes include alterations to the dynamics between the plasma membrane and the actin cytoskeleton, and subversion of the membrane-associated pathways that are involved in vesicle trafficking.

  • Many bacterial effectors manipulate phosphoinositide (PI) homeostasis at the plasma membrane to destabilize actin dynamics and alter the morphology of the membrane. This facilitates the entry of pathogens or, in other cases, damages the cells by disrupting membrane integrity and eventually leading to rapid cell lysis in the later stage of infection.

  • Some pathogens use bacterial phosphatases or PI adaptor proteins to form intracellular vacuoles that are derived from host membranes in order to establish a replicative niche. Altered PI levels at the surfaces of these vacuoles as a result of the activity of bacterial phosphatases can block phagosomal maturation to avoid lysosomal fusion.

  • The GTPase signalling pathway is often targeted by bacterial pathogens to manipulate the actin cytoskeleton and endosomal trafficking. RAB GTPases, which have an important role in vesicular trafficking pathways, are recruited to bacterium-containing vacuoles, where their active state can be differentially regulated by effectors.

  • Bacterial effectors mimic GTPase-activating protein (GAP) or guanine nucleotide exchange factor (GEF) activity to target RHO-family GTPases that are key regulators of actin dynamics. This results in loss of cell shape, motility and ability to phagocytose pathogens.

  • Autophagy is one of the cellular defence mechanisms against the invasion of pathogenic bacteria. However, some pathogens have evolved strategies to subvert autophagy to their own advantage by establishing autophagic vesicles as their replicative niche. This allows them to survive inside host cells and avoid lysosomal degradation.

  • Some bacterial effectors are speculated to induce autophagy during infection. This may not only protect the bacteria from degradative enzymes and immune responses, but also provide nutrients from cellular debris. For extracellular pathogens, inducing autophagy helps prevent phagocytosis.

Abstract

Bacterial pathogens interact with host membranes to trigger a wide range of cellular processes during the course of infection. These processes include alterations to the dynamics between the plasma membrane and the actin cytoskeleton, and subversion of the membrane-associated pathways involved in vesicle trafficking. Such changes facilitate the entry and replication of the pathogen, and prevent its phagocytosis and degradation. In this Review, we describe the manipulation of host membranes by numerous bacterial effectors that target phosphoinositide metabolism, GTPase signalling and autophagy.

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Figure 1: Lifestyles for pathogenic bacteria.
Figure 2: Bacterial effectors that modulate host phosphoinositide metabolism.
Figure 3: Bacterial effectors that target GTPase signalling pathways.
Figure 4: Bacterial pathogens that subvert the autophagic pathway.

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Acknowledgements

We thank N. Alto and members of the Orth laboratory for their advice and discussion. K.O., H.H. and A.S. are supported by grants from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (R01-AI056404 and R01-AI087808) and the Welch Foundation (I-1561). A.S. is supported by the Howard Hughes Medical Institute Med to Grad Initiative. K.O. is a Burroughs Wellcome Investigator in Pathogenesis of Infectious Disease and a W. W. Caruth, Jr. Biomedical Scholar.

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  1. Hyeilin Ham and Anju Sreelatha: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Hyeilin Ham, Anju Sreelatha & Kim Orth

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  1. Hyeilin Ham
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  2. Anju Sreelatha
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  3. Kim Orth
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Correspondence to Kim Orth.

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Glossary

Type III secretion system

(T3SS). A multisubunit, needle-like apparatus that is found in various Gram-negative bacterial pathogens of plants and animals, and penetrates the host cell membrane to translocate effectors into the host cytoplasm during infection.

Type IV secretion system

(T4SS). A multisubunit transporter complex that is found in various Gram-negative bacterial pathogens and delivers substrate molecules, including effector proteins and DNA, into the host cell.

Bacterial effectors

Proteins that are secreted by bacterial pathogens and used as virulence factors during infection.

Pilus

A hair-like projection that attaches one bacterium to another.

GTPase

A protein that cycles between the active, GTP-bound state and the inactive, GDP-bound state to regulate various cellular processes such as vesicle trafficking and actin dynamics. These enzymes are tightly regulated by GTPase-activating proteins and guanine nucleotide exchange factors.

Phosphatidylinositol

A small, negatively charged phospholipid molecule that is a key component of cell membranes and serves various roles in mediating signalling transduction.

Filopodia

Actin-rich cellular projections that aid in motility and environment sensing in eukaryotic cells.

F-actin

The filamentous form of actin; a polymer of globular monomeric actin.

Phagosome

A vacuole that is derived from the outer cell membrane of a host cell and that has engulfed a foreign particle.

Endoplasmic reticulum exit sites

Periphery regions of the endoplasmic reticulum where cargo proteins are exported in vesicles.

RAB GTPase

A member of the RAB family of small monomeric GTPases that are involved in the regulation of vesicle trafficking.

GTPase-activating proteins

(GAPs). A family of proteins that accelerate GTPase-mediated hydrolysis of GTP to GDP.

Guanine nucleotide exchange factors

(GEFs). A family of proteins that induce GTPases to exchange GTP for GDP, resulting in activation of the GTPases.

RHO

A family of small monomeric GTPases (including the RHO proteins, RAC proteins and CDC42) that are involved in the regulation of actin dynamics.

Guanine nucleotide dissociation inhibitor

(GDI). A protein that binds to a GDP-bound GTPase and holds it in an inactive, soluble state in the cytoplasm.

AMPylation

A post-translational modification that involves the covalent attachment of AMP to a threonine or tyrosine residue on a protein substrate, resulting in an altered activity of the modified protein.

Stress fibres

Bundles of actin filaments.

Lamellipodia

Dynamic actin-rich regions on the edge of a cell that aid in cell motility.

Autophagosome

A double-membraned compartment that contains host cytoplasm and organelles and is formed in cells undergoing autophagy.

LC3

(Microtubule-associated protein light chain 3). The cytosolic form of this protein, LC3-I, is lipidated and conjugated to phosphatidylethanolamine to form LC3-II, which then localizes to autophagosomal membranes. The increase in the conversion of LC3-I to LC3-II can be monitored as a marker for the induction of autophagy.

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Ham, H., Sreelatha, A. & Orth, K. Manipulation of host membranes by bacterial effectors. Nat Rev Microbiol 9, 635–646 (2011). https://doi.org/10.1038/nrmicro2602

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