The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

Abstract

To prevail in the interaction with eukaryotic hosts, many bacterial pathogens use protein secretion systems to release virulence factors at the host–pathogen interface and/or deliver them directly into host cells. An outstanding example of the complexity and sophistication of secretion systems and the diversity of their protein substrates, effectors, is the Defective in organelle trafficking/Intracellular multiplication (Dot/Icm) Type IVB secretion system (T4BSS) of Legionella pneumophila and related species. Legionella species are facultative intracellular pathogens of environmental protozoa and opportunistic human respiratory pathogens. The Dot/Icm T4BSS translocates an exceptionally large number of effectors, more than 300 per L. pneumophila strain, and is essential for evasion of phagolysosomal degradation and exploitation of protozoa and human macrophages as replicative niches. Recent technological advancements in the imaging of large protein complexes have provided new insight into the architecture of the T4BSS and allowed us to propose models for the transport mechanism. At the same time, significant progress has been made in assigning functions to about a third of L. pneumophila effectors, discovering unprecedented new enzymatic activities and concepts of host subversion. In this review, we describe the current knowledge of the workings of the Dot/Icm T4BSS machinery and provide an overview of the activities and functions of the to-date characterized effectors in the interaction of L. pneumophila with host cells.

Protein sociology of ProA, Mip and other secreted virulence factors at the Legionella pneumophila surface

“…The most important secretion system, which is essential for the whole life cycle of L. pneumophila, is the Dot/Icm type IVB secretion system (T4SS) (Lockwood et al, 2022). Translocated effector proteins control the bacterial uptake and egress, disrupt the phagolysosome fusion, and manipulate many critical processes in the eukaryotic cell, such as vesicle transport, signal transduction, gene expression and protein translation, ubiquitination, cytoskeleton dynamics, autophagy, apoptosis pathways, and host defense (Berger and Isberg, 1993;Segal et al, 2005;Michard and Doublet, 2015;Hilbi et al, 2017;Allgood and Neunuebel, 2018;Schuhmacher et al, 2018;Yu et al, 2018;Kitao et al, 2020).…”

“…With more than 300 substrates the Dot/Icm type IVB secretion system secretes the largest repertoire of virulence-associated effectors of any pathogen species known to date (Al-Quadan et al, 2012;Lockwood et al, 2022). They enable the bacterium to infect many hosts from different phyla and with evolutionary distance (Boamah et al, 2017;Graells et al, 2018;Moreno et al, 2019).…”

Intracellular persister: A stealth agent recalcitrant to antibiotics

“…In addition to the defensive mode, the intracellular L. pneumophila persisters execute a specific offensive virulence program that involves a portfolio of only a few tens of effectors (Personnic et al, 2019), out of 400 substrates (Burstein et al, 2016;Finsel and Hilbi, 2015;Personnic et al, 2016), that are translocated into the host cell cytosol via the Icm/Dot type 4 secretion system (T4SS) in order to disable host functions. Notably, the persister produce SidC that uses an N-terminal E3 Ub ligase domain to mono-ubiquinate the cellular GTPase Rab1 and mono-ubiquinate and poly-ubiquitinate the GTPase Rab10 (Lockwood et al, 2022). Thereby, the persisters evade the bactericidal phago-lysosomal pathway by redirecting the vacuolar maturation route toward the safer secretory pathway (Figure 1B).…”

Legionella pneumophila: The Journey from the Environment to the Blood

“…There are two subclasses of the T4SS, namely the T4SS -A (Lvh) and the T4SS-B (Dot/Icm:(Defect in organelle trafficking/Intracellular multiplication). The Dot/Icm genes encode Dot/Icm secretory system proteins [ 67 ], and are vital for organelle trafficking and intracellular multiplication [ 80 ], while the Lvh secretion system contains genes encoding mobility factors and enzymes [ 81 ]. Furthermore, the Lvh can functionally replace defective Dot/Icm.…”