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  • Review Article
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Legionella and Coxiella effectors: strength in diversity and activity

Nature Reviews Microbiology volume 15, pages 591–605 (2017)Cite this article

Subjects

Key Points

  • Legionella pneumophila and Coxiella burnetii are two evolutionarily related intracellular bacterial pathogens that reside in distinct compartments in host cells during infection. Successful infection by both pathogens requires a functionally exchangeable type IV secretion system called Dot/Icm, which translocates hundreds of virulence factors, termed effectors, into host cells.

  • The majority of Legionella spp. and Coxiella spp. effectors are unique to these pathogens, and functional redundancy exists among many of them. Functional domains that are associated with most of these effectors are enigmatic and cannot be readily predicted by currently available bioinformatics tools.

  • Legionella spp. and Coxiella spp. promote intracellular bacterial replication by interfering with host gene expression through effectors that impose epigenetic modifications on host chromatin by different mechanisms.

  • L. pneumophila extensively manipulates the early phases of the secretory branch of the host vesicle trafficking pathway by hijacking the activity of key regulatory proteins such as RAB small GTPases via multiple effectors.

  • L. pneumophila effectors function coordinately to alter the composition of lipids, such as phosphoinositides, on the vacuole that contains the bacterium and other organelles to facilitate its intracellular growth.

  • L. pneumophila co-opts the ubiquitin network of host cells by effectors that function through diverse biochemical mechanisms, including the SidE family effectors, which catalyse ubiquitylation by an E1 enzyme and E2 enzyme-independent mechanism, which represents a paradigm shift in our understanding of this important post-translational modification.

Abstract

Legionella pneumophila and Coxiella burnetii are two evolutionarily related intracellular pathogens that use the Dot/Icm type IV secretion system to translocate effectors into host cells. These effectors are essential for the establishment of membrane-bound compartments known as replication vacuoles, which enable the survival and replication of bacteria inside host cells. The effectors interfere with diverse signalling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, to promote pathogen survival. In this Review, we explore Dot/Icm effectors from L. pneumophila and C. burnetii as key virulence factors, and we examine the biochemical and cell biological functions of these effectors and their roles in our understanding of bacterial virulence.

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Figure 1: The trafficking routes of Legionella pneumophila and Coxiella burnetii in phagocytes.
Figure 2: Modulation of host vesicle trafficking by Dot/Icm effectors of Legionella pneumophila.
Figure 3: Host cellular processes that are targeted by Coxiella burnetii effectors.
Figure 4: The mechanisms of ubiquitin activation and ligation by ATP and NAD.
Figure 5: Multiple pathways contribute to the enrichment of phosphatidylinositol 4-phosphate on the LCV.

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Acknowledgements

The authors thank members of their laboratory for helpful discussions. They also thank their colleagues and collaborators S. Banga, X. Shen, Y. Liu, Y. Tan, L. Xu, W. Zhu, M. Sheedlo, Y. Mao (Cornell University), R. Vance (UC Berkeley), X. Liu (Peking University), J. Samuel (Texas A&M University), C. Das (Purdue University) and E. Nakayasu (Pacific Northwest National Laboratory) for productive collaborations and discussion. The authors apologize to colleagues whose works could not be cited owing to space limitation. Work in the author's laboratory was supported by US National Institute of Allergy and Infectious Disease (grants AI103168 and AI105714).

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Authors and Affiliations

  1. Center of Infection and Immunity, The First Hospital, Jilin University, Changchun, 130001, China

    Jiazhang Qiu & Zhao-Qing Luo

  2. Purdue Institute for Inflammation, Immunology and Infectious Diseases, Purdue University,

    Jiazhang Qiu & Zhao-Qing Luo

  3. Department of Biological Sciences, Purdue University, West Lafayette, 47907, Indiana, USA

    Jiazhang Qiu & Zhao-Qing Luo

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  1. Jiazhang Qiu
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Correspondence to Zhao-Qing Luo.

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The mechanisms of induction of host gene expression by Legionella pneumophila effectors. (PDF 374 kb)

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Glossary

Lysosome

A cellular compartment that is characterized by low lumen pH (4.5–5.0) and the harbouring of hydrolytic enzymes that are capable of breaking down biomolecules. In addition to degrading biomaterials, the lysosome also has crucial roles in many important cellular processes, such as cell signalling and metabolism.

Phagolysosome

A cellular compartment that is formed by the fusion of a lysosome with a phagosome generated during phagocytosis.

Autophagosome

A structure with double-layer membranes that is formed during autophagy.

Type IV secretion systems

A family of specialized transporters that consist of multiple proteins that span the two bacterial cell membranes and transfer DNA–protein complexes or proteins from the cytosol of donor bacterial cells to the cytosol of eukaryotic or recipient bacterial cells.

Effectors

Secreted proteins used by pathogenic or symbiotic microorganisms, including bacteria, fungi and parasites, to change the physiology of the host cell, thus enabling successful colonization.

Secretory pathway

A branch of the vesicle trafficking pathway that functions to deliver newly synthesized proteins or lipids from the endoplasmic reticulum to various cellular locations, including the extracellular milieu.

Endosomal trafficking

A cellular process that is involved in the transport of internalized cargoes (bacteria, inert particles or receptor–ligand complexes) carried in the lumen of membrane-bound compartments to their final destinations, such as the trans-Golgi site, the plasma membrane or the lysosome.

Endosomes

Membrane-bound compartments that are formed through several complex processes collectively known as endocytosis; it is found in the cytoplasm of almost every eukaryotic cell. Depending on its maturation stage, they can be divided into early endosomes, late endosomes and recycling endosomes.

GTPases

A large family of enzymes that can bind to and hydrolyse GTP. These enzymes often function as molecular switches that assume an on and an off status by binding to GTP and GDP, respectively.

AMPylation

A process, also known as adenylylation, in which the adenosine monophosphate (AMP) moiety from ATP is covalently linked to a substrate protein. This modification alters the function of the target protein and can be reversed by specific enzymes.

Phosphorylcholination

(PCylation). A chemical modification in which the phosphorylcholine moiety often from CDP-choline is enzymatically attached to the backbone of a protein (mostly in eukaryotes). The modification alters the activity of the target molecules and can be reversed by specific enzymes.

Fic proteins

A large family of proteins that share a structural motif originally associated with a protein in a mutant that displays a filamentous phenotype in media containing cyclic AMP. Those proteins that function to transfer the AMP moiety from ATP to target proteins are called AMPylators.

E3 ubiquitin ligases

One of the three enzymes that are involved in the biochemical reactions in the canonical ubiquitylation mechanism that modifies proteins by adding the ubiquitin modifier. They are important in substrate recognition.

Retromer

A complex formed by five different proteins (a heteropentamer) that anchors on the cytosolic face of endosomes; it participates in a wide range of physiological, developmental and pathological processes by mediating retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network.

Clathrin

A protein important for the generation of coated vesicles; it functions by forming a triskelion shape composed of three clathrin heavy chains and three light chains. Clathrin-coated vesicles selectively sort cargo at the cell membrane, trans-Golgi network and endosomal compartments for multiple membrane traffic pathways.

ADP-ribosylation

A biochemical reaction that transfers the ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD) to protein targets. It is often catalysed by bacterial toxins that contain a mono-ADP-ribosyltransferase (mART) motif.

Reticulon

A group of evolutionarily conservative proteins that reside predominantly in the endoplasmic reticulum; their primary role is to promote membrane curvature.

Xenophagy

A form of autophagy that specifically targets and eliminates non-host entities, such as invading pathogens.

Unfolded protein response

(UPR). A cellular stress response that is activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. It functions to alleviate the damage caused by such accumulation by halting protein translation, degrading misfolded proteins and producing molecular chaperones that facilitate protein folding.

Inflammasome

A multiprotein complex that functions to activate caspase 1 and induce inflammation in response to cues released by invading pathogens or host cells. One major component of inflammasome is constituted by members of the nucleotide-binding oligomerization domain-like receptors (NOD-like receptors or NLRs) that define its feature, physiological role and name. For example, the one containing NLRP3 is called the NLRP3 inflammasome.

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Qiu, J., Luo, ZQ. Legionella and Coxiella effectors: strength in diversity and activity. Nat Rev Microbiol 15, 591–605 (2017). https://doi.org/10.1038/nrmicro.2017.67

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