Pathogenicity and Virulence ofLegionella: Intracellular replication and host response

Virulence, Journal Year: 2021, Volume and Issue: 12(1), P. 1122 - 1144

Published: April 12, 2021

Bacteria of the genus Legionella are natural pathogens amoebae that can cause a severe pneumonia in humans called Legionnaires' Disease. Human disease results from inhalation Legionella-contaminated aerosols and subsequent bacterial replication within alveolar macrophages. pathogenicity has resulted extensive co-evolution with diverse genera amoebae. To replicate intracellularly, generates replication-permissive compartment Legionella-containing vacuole (LCV) through concerted action hundreds Dot/Icm-translocated effector proteins. In this review, we present collective overview including infection mechanisms, secretion systems, translocated function. We also discuss innate adaptive immune responses to L. pneumophila, implications genome diversity future avenues for field.

Language: Английский

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Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Nov. 2, 2020

Legionella pneumophila extensively modulates the host ubiquitin network to create Legionella-containing vacuole (LCV) for its replication. Many of virulence factors function as ligases or deubiquitinases (DUBs). Here, we identify Lem27 a DUB that displays preference diubiquitin formed by K6, K11, K48. is associated with LCV where it regulates Rab10 ubiquitination in concert SidC and SdcA, two bacterial E3 ligases. Structural analysis complex an active fragment substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals harbors fold resembling those OTU1 subfamily Cys-His catalytic dyad recognizes via extensive hydrogen bonding at six contact sites. Our results establish functions regulate protein on L. phagosomes counteracting activity

Language: Английский

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

Microbiology, Journal Year: 2022, Volume and Issue: 168(5)

Published: May 23, 2022

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

Language: Английский

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Regulation of Host-Pathogen Interactions via the Ubiquitin System

Annual Review of Microbiology, Journal Year: 2022, Volume and Issue: 76(1), P. 211 - 233

Published: Sept. 8, 2022

Ubiquitination is a posttranslational modification that regulates multitude of cellular functions. Pathogens, such as bacteria and viruses, have evolved sophisticated mechanisms evade or counteract ubiquitin-dependent host responses, even exploit the ubiquitin system to their own advantage. This largely done by numerous pathogen virulence factors encode E3 ligases deubiquitinases, which are often used weapons in pathogen–host cell interactions. Moreover, upon attack, signaling networks undergo major changes protect cell, including coordination innate immunity, remodeling organelles, reorganization cytoskeleton, reprogramming metabolic pathways restrict growth pathogen. Here we provide mechanistic insights into regulation host-pathogen interactions how it affects bacterial viral pathogenesis organization response cell.

Language: Английский

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The evolution and role of eukaryotic-like domains in environmental intracellular bacteria: the battle with a eukaryotic cell

FEMS Microbiology Reviews, Journal Year: 2022, Volume and Issue: 46(4)

Published: Feb. 14, 2022

Abstract Intracellular pathogens that are able to thrive in different environments, such as Legionella spp. preferentially live protozoa aquatic environments or environmental Chlamydiae replicate either within a range of animals, possess plethora cellular biology tools influence their eukaryotic host. The host manipulation evolved the interaction with confer these bacteria capacity also infect phylogenetically distinct cells, macrophages, and thus they can be human pathogens. To manipulate cell, use protein secretion systems molecular effectors. Although effectors encoded bacteria, expressed function context often mimicking inhibiting proteins. Indeed, many have eukaryotic-like domains. In this review, we propose main pathways intracellular need subvert order establish cell replication niche chromatin remodelling, ubiquitination signalling modulation protein–protein interactions via tandem repeat We then provide mechanistic insight into how proteins might evolved. Finally, highlight number domains is considerably higher than specialized an isolated niche, obligate As mimics critical components host–pathogen interactions, distribution suggests environment has selected them.

Language: Английский

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The Legionella Effector SdjA Is a Bifunctional Enzyme That Distinctly Regulates Phosphoribosyl Ubiquitination

mBio, Journal Year: 2021, Volume and Issue: 12(5)

Published: Sept. 7, 2021

Legionella pneumophila promotes its survival and replication in phagocytes by actively modulating cellular processes using effectors injected into host cells Dot/Icm type IV secretion system. Many of these function to manipulate the ubiquitin network infected cells, thus contributing biogenesis Legionella-containing vacuole (LCV), which is permissive for bacterial replication. Among these, members SidE effector family (SidEs) catalyze ubiquitination functionally diverse proteins a mechanism that chemically distinct from canonical three-enzyme cascade. The activity SidEs regulated two mechanisms: reversal phosphoribosyl DupA DupB direct inactivation SidJ, calmodulin-dependent glutamylase. In many L. strains, SidJ belongs two-member protein family. Its homolog SdjA appears differently despite high-level similarity their primary sequences. Here, we found bifunctional enzyme exhibits activities toward It inhibits SdeB SdeC glutamylation. Unexpectedly, it also functions as deglutamylase reverses SidJ-induced glutamylation on SdeA. Our results reveal an can completely opposite biochemical reactions, highlights regulation IMPORTANCE One unique feature existence families with similarity. Whereas some are redundant, suggested sequences, relationship between SdjA, family, has remained mysterious. Despite sharing 57% identity, sdjA cannot complement defects virulence displayed mutant lacking sidJ. calmodulin (CaM)-dependent glutamylase activity. dual protein: CaM-dependent against but SdeA been modified indicating fine-tune SidEs. These findings have paved way future structural functional analysis may novel isopeptide bond cleavage provide insights study evolution.

Language: Английский

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Ubiquitin and Legionella: From bench to bedside

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 132, P. 230 - 241

Published: Feb. 15, 2022

Legionella pneumophila, a Gram-negative intracellular bacterium, is one of the major causes Legionnaires' disease, specific type atypical pneumonia. Despite intensive research efforts that elucidated many relevant structural, molecular and medical insights into Legionella's pathogenicity, disease continues to present an ongoing public health concern. virulence based on its ability simultaneously hijack multiple pathways host cell ensure fast replication dissemination. usurps ubiquitin system through effector proteins, using advantage both conventional unconventional (phosphoribosyl-linked) ubiquitination, thus providing optimal conditions for replication. In this review, we summarize current understanding L. pneumophila from medical, biochemical perspectives. We describe clinical presentation, diagnostics treatment, as well host-pathogen interactions, with emphasis target upon infection. Furthermore, interdisciplinary use innovative technologies enables better pathogenesis provides new opportunities treatment prevention.

Language: Английский

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In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 22, 2024

Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given potential as novel therapeutic targets, it is essential fully understand mechanisms action. Traditionally, observed effects resulting from deficiencies deubiquitinases (DUBs) UBL proteases have often attributed misregulation substrate modification by UBLs. Therefore, much research focused on understanding catalytic activities these proteins. However, this view overlooked possibility DUBs might also significant non-catalytic functions, which more prevalent than previously believed urgently require further investigation. Moreover, multiple examples shown either selective loss only protease activity complete absence can different functional physiological consequences. Furthermore, contain domains binding motifs not modulate but mediate entirely functions. This review aims shed light non-catalytic, moonlighting functions proteases, extend beyond hydrolysis chains just beginning emerge.

Language: Английский

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Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

Frontiers in Microbiology, Journal Year: 2021, Volume and Issue: 12

Published: Dec. 22, 2021

Ubiquitination is a commonly used post-translational modification (PTM) in eukaryotic cells, which regulates wide variety of cellular processes, such as differentiation, apoptosis, cell cycle, and immunity. Because its essential role immunity, the ubiquitin network common target infectious agents, have evolved various effective strategies to hijack co-opt signaling for their benefit. The intracellular pathogen Legionella pneumophila represents one example; it utilizes large cohort virulence factors called effectors modulate diverse resulting formation compartment Legionella-containing vacuole (LCV) that supports replication. Many these function re-orchestrate with distinct biochemical activities. In this review, we highlight recent progress mechanism action L. involved ubiquitination discuss roles bacterial host biology.

Language: Английский

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Bacterial nucleomodulins: A coevolutionary adaptation to the eukaryotic command center

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(1), P. e1009184 - e1009184

Published: Jan. 21, 2021

Through long-term interactions with their hosts, bacterial pathogens have evolved unique arsenals of effector proteins that interact specific host targets and reprogram the cell into a permissive niche for pathogen proliferation. The targeting nucleus modulation nuclear processes is an emerging theme among pathogens. These been termed in recent years as “nucleomodulins.” first nucleomodulins were discovered phytopathogens Agrobacterium Xanthomonas , where functioned eukaryotic transcription factors or integrated themselves DNA to promote tumor induction, respectively. Numerous recently identified mammalian Bacterial are family target components command center through various mechanisms. mechanisms include: chromatin dynamics, histone modification, methylation, RNA splicing, replication, cycle, signaling pathways. Nucleomodulins may induce short- epigenetic modifications cell. In this extensive review, we discuss current knowledge from plant While many already identified, continued research instrumental understanding action role they play during progression pathogenesis. study will enhance our effects on protein homeostasis, transcriptional landscapes, overall epigenome.

Language: Английский

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