Molecular Cell, Journal Year: 2022, Volume and Issue: 82(10), P. 1781 - 1783
Published: May 1, 2022
Language: Английский
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
Citations
33
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: March 19, 2024
Abstract ADP-ribosylation is a reversible post-translational modification involved in various cellular activities. Removal of requires (ADP-ribosyl)hydrolases, with macrodomain enzymes being major family this category. The pathogen Legionella pneumophila mediates atypical ubiquitination host targets using the SidE effector process that involves ubiquitin on arginine 42 as an obligatory step. Here, we show MavL regulates pathway by reversing ADP-ribosylation, likely to minimize potential detrimental effects caused modified ubiquitin. We determine crystal structure ADP-ribose-bound MavL, providing structural insights into recognition ADP-ribosyl group and catalytic mechanism its removal. Further analyses reveal DUF4804 class MavL-like whose representative members unique selectivity for mono-ADP-ribosylated residue synthetic substrates. find such are also present eukaryotes, exemplified two previously uncharacterized (ADP-ribosyl)hydrolases Drosophila melanogaster . Crystal structures several proteins provide specificity shared mode ADP-ribose interaction distinct from characterized macrodomains. Collectively, our study reveals new regulatory layer SidE-catalyzed expands current understanding enzymes.
Language: Английский
Citations
6
PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(5), P. e1011783 - e1011783
Published: May 13, 2024
Legionella pneumophila strains harboring wild-type rpsL such as Lp02 WT cannot replicate in mouse bone marrow-derived macrophages (BMDMs) due to induction of extensive lysosome damage and apoptosis. The bacterial factor directly responsible for inducing cell death the host involved initiating signaling cascade that leads remain unknown. Similarly, factors may alleviate induced by these have not yet been investigated. Using a genome-wide CRISPR/Cas9 screening, we identified Hmg20a Nol9 important restricting strain BMDMs. Depletion protects from infection-induced lysosomal apoptosis, allowing productive replication. restriction imposed was mediated repressing expression several endo-lysosomal proteins, including small GTPase Rab7. We found SUMOylated Rab7 is recruited phagosome via SulF, Dot/Icm effector harbors SUMO-interacting motif (SIM). Moreover, overexpression rescues intracellular growth Our results establish L . exploits network biogenesis its
Language: Английский
Citations
5
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: May 20, 2025
Adenosine 5'-triphosphate (ATP) is the currency of energy in cells; it plays essential roles virtually all cellular processes, ranging from basic metabolism to signaling development and disease. The opportunistic bacterial pathogen Legionella pneumophila utilizes Dot/Icm type IV secretion system deliver over 300 effectors into host cells, some which utilize ATP perform biochemical reactions catalyzed by their unique enzymatic activities. However, whether L. directly regulates level cells unknown. Here, we discover that substrate Ceg14 (Lpg0437, a.k.a. SidL) an ATP/dATPase, after being activated protein actin, efficiently converts dATP adenosine deoxyadenosine monophosphate, respectively a mechanism requires its S-HxxxE (x, any amino acid) motif. activity regulated metaeffector AnkJ (Lpg0436, LegA11), inhibits ATPase via direct protein-protein interactions. impose temporal regulation levels pneumophila-infected cells. Our results demonstrate modulates create environment permissive for growth.
Language: Английский
Citations
0
mLife, Journal Year: 2022, Volume and Issue: 1(1), P. 51 - 65
Published: March 1, 2022
Abstract The mitochondrion is an important signaling hub that governs diverse cellular functions, including metabolism, energy production, and immunity. Among the hundreds of effectors translocated into host cells by Dot/Icm system Legionella pneumophila , several are targeted to mitochondria but function most them remains elusive. Our recent study found effector Ceg3 inhibits activity ADP/ATP translocases (ANTs) ADP‐ribosylation (ADPR). Here, we show effect antagonized Larg1, encoded lpg0081 a gene situated next ceg3 . Larg1 functions reverse Ceg3‐mediated ADPR ANTs cleaving N‐glycosidic bond between moiety modified arginine residues in ANTs, leading restoration their exchange. Structural analysis its complex with reveals this glycohydrolase harbors unique macrodomain catalyzes removal modification on ANTs. results also demonstrate together Ceg3, imposes temporal regulation reversible during L. infection.
Language: Английский
Citations
11
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown
Published: Oct. 31, 2023
Summary L. pneumophila strains harboring wild-type rpsL such as Lp02 WT cannot replicate in mouse bone marrow-derived macrophages (BMDMs) due to induction of extensive lysosome damage and apoptosis. The mechanism this unique infection-induced cell death remains unknown. Using a genome-wide CRISPR/Cas9 screening, we identified Hmg20a Nol9 host factors important for restricting strain BMDMs. Depletion protects from lysosomal apoptosis, allowing productive bacterial replication. restriction imposed by was mediated repressing the expression several endo-lysosomal proteins, including small GTPase Rab7. We found that SUMOylated Rab7 is recruited phagosome via SulF, Dot/Icm effector harbors SUMO-interacting motif (SIM). Moreover, overexpression rescues intracellular growth Our results establish exploits network biogenesis its
Language: Английский
Citations
4
Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14
Published: Sept. 11, 2024
infection, the causative agent of Legionnaires' disease, represents a significant threat to human health. The pathogenesis this infection is intricately linked complex interactions between bacterium and its host, resulting in profound metabolic perturbations. Central these shifts bacterium's modulation lipid metabolism, with changes synthesis breakdown modifying membrane composition function. These alterations can influence cellular signaling immune responses, further contributing disease progression. It also disrupts glucose utilization altering energy production responses. Additionally,
Language: Английский
Citations
1
Molecular Microbiology, Journal Year: 2023, Volume and Issue: 119(6), P. 677 - 686
Published: May 1, 2023
Abstract Protein post‐translational modifications (PTMs), such as ADP‐ribosylation and phosphorylation, regulate multiple fundamental biological processes in cells. During bacterial infection, effector proteins are delivered into host cells through dedicated secretion systems can modulate important cellular pathways by covalently modifying their targets. These strategies enable intruding bacteria to subvert various processes, thereby promoting own survival proliferation. Despite rapid expansion of our understanding effector‐mediated PTMs cells, analytical measurements these molecular events still pose significant challenges the study host–pathogen interactions. Nevertheless, with major technical breakthroughs last two decades, mass spectrometry (MS) has evolved be a valuable tool for detecting protein mapping modification sites. Additionally, large‐scale PTM profiling, facilitated different enrichment prior MS analysis, allows high‐throughput screening enzymatic substrates effectors. In this review, we summarize advances studies representative (i.e., phosphorylation) catalyzed effectors during infection. Importantly, will discuss ever‐increasing role how latest MS‐based tools aid future booming area pathogenic bacteria–host
Language: Английский
Citations
2
Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 25, 2024
Ubiquitination and ADP-ribosylation are two types of post-translational modification (PTM) involved in regulating various cellular activities. In a striking example direct interplay between ubiquitination ADP-ribosylation, the bacterial pathogen Legionella pneumophila uses its SidE family secreted effectors to catalyze an NAD+-dependent phosphoribosyl host substrates process involving intermediary formation ADP-ribosylated ubiquitin (ADPR-Ub). This noncanonical pathway is finely regulated by multiple ensure balanced subjugation. Among regulatory effectors, macrodomain effector MavL has been recently shown reverse Ub regenerate intact Ub. Here, we briefly outline emerging knowledge on tap into cases cross-talk these PTMs. The chemistry ADP-ribose context PTM reversal mechanisms then highlighted. Lastly, focusing recent structural studies MavL-mediated strive deduce distinct regarding catalysis product release this reaction.
Language: Английский
Citations
0
Medicina, Journal Year: 2022, Volume and Issue: 58(9), P. 1150 - 1150
Published: Aug. 24, 2022
In children, the incidence of Legionnaires’ disease (LD) is unknown, hospital-acquired LD associated with clinical risk factors and environmental risk, children cell-mediated immune deficiency are at high infection. Both newborns were born in same delivery room; stayed hospital room where they cared for, bathed, breastfed; male; on time, normal birth weight, Apgar score birth; survived this severe infection (L. pneumophila, serogroup 2-15) but different courses. neonate 1, bleeding brain, thrombosis deep pelvic veins, necrosis lungs, which left behind cystic cavernous changes found, while 2 suffered from pneumonia alone. The only difference for between these two number days illness until start azithromycin treatment (sixth versus third day illness). We suggest that a change guidelines diagnosing treating community-acquired needed terms mandatory routine testing Legionella pneumophila. Early initiation macrolide therapy crucial outcome newborn.
Language: Английский
Citations
2