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.

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. Access through your institution Buy or subscribe This is a

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* Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS COMPARATIVE ANALYSIS OF _LEGIONELLA LYTICA_ GENOME

IDENTIFIES SPECIFIC METABOLIC TRAITS AND VIRULENCE FACTORS Article Open access 14 February 2025 THE ANTI-APOPTOTIC _COXIELLA BURNETII_ EFFECTOR PROTEIN ANKG IS A STRAIN SPECIFIC VIRULENCE

FACTOR Article Open access 21 September 2020 MECHANISM OF EFFECTOR CAPTURE AND DELIVERY BY THE TYPE IV SECRETION SYSTEM FROM _LEGIONELLA PNEUMOPHILA_ Article Open access 08 June 2020

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Central  Google Scholar  Download references 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). AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Center of Infection and Immunity, The First Hospital, Jilin University, Changchun, 130001, China Jiazhang Qiu & Zhao-Qing Luo * Purdue Institute for

Inflammation, Immunology and Infectious Diseases, Purdue University, Jiazhang Qiu & Zhao-Qing Luo * Department of Biological Sciences, Purdue University, West Lafayette, 47907, Indiana,

USA Jiazhang Qiu & Zhao-Qing Luo Authors * Jiazhang Qiu View author publications You can also search for this author inPubMed Google Scholar * Zhao-Qing Luo View author publications You

can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Zhao-Qing Luo. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION S1 (FIGURE) The mechanisms of induction of host gene expression by _Legionella pneumophila_ effectors. (PDF 374 kb)

POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 POWERPOINT SLIDE FOR TABLE 1

POWERPOINT SLIDE FOR TABLE 2 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. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Qiu, J., Luo, ZQ. _Legionella_ and _Coxiella_ effectors: strength in diversity and activity. _Nat Rev Microbiol_ 15, 591–605 (2017).

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