mSystems, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 11, 2024
uses over 300 translocated effector proteins to rewire host cells during infection and create a replicative niche for intracellular growth. To date, several studies have identified
Language: Английский
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: July 15, 2024
Abstract The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, of the SidE family interfere protein ubiquitination in a process that involves production phosphoribosyl ubiquitin (PR-Ub). Here, we show effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional (ADP-ribosyl)hydrolase MavL, thus maintaining homeostasis infected cells. Upon being activated actin, also undergoes self-AMPylation on tyrosine residues. activity requires motif consisting Ser, His Glu (SHxxxE) present large toxins from pathogens. Thus, our study sheds light mechanisms maintains identifies enzymes capable AMPylation.
Language: Английский
Citations
10
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
34
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
Citations
27
Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 18
Published: Aug. 10, 2022
Extensive use of substances derived from natural sources has been documented in the treatment colorectal cancer (CRC). Lysionotin (Lys) is a flavonoid present flowers and leaves Gesneriaceae family plants. Despite its various pharmacological properties, which include neuroprotective, pro, antimalarial, anticancer effects, therapeutic advantages Lys for CRC remain uncertain. In this study, we demonstrated that successfully inhibited cell proliferation, migration, invasion HCT116 SW480 cells vitro. Intriguingly, significant ferroptosis reactive oxygen species (ROS) accumulation were induced by treatment, whereas antagonism Liproxstatin-1 (Lip1) pretreatment retarded anti-CRC effects Lys. addition, reduced amount Nrf2 protein increasing rate at it degraded. Overexpression rescued ferroptosis, suggesting signaling crucial determinant whether induces cells. We also revealed suppressed tumor growth vivo without obvious adverse on main organs mice. conclusion, our results discovered to exert antitumor modulating signaling, providing potential approach prevention cancer.
Language: Английский
Citations
27
eLife, Journal Year: 2022, Volume and Issue: 11
Published: Feb. 17, 2022
The cytoskeleton network of eukaryotic cells is essential for diverse cellular processes, including vesicle trafficking, cell motility, and immunity, thus a common target bacterial virulence factors. A number effectors from the pathogen Legionella pneumophila have been shown to modulate function host actin construct Legionella-containing vacuole (LCV) permissive its intracellular replication. In this study, we found that Dot/Icm effector Lem8 (Lpg1290) protease whose activity catalyzed by Cys-His-Asp motif known be associated with biochemical activities. Intriguingly, interacts regulatory protein 14-3-3ζ, which activates activity. Furthermore, undergoes self-cleavage in process requires 14-3-3ζ. We identified Pleckstrin homology-like domain-containing Phldb2 involved organization as demonstrated plays role inhibition migration attacking Phldb2.
Language: Английский
Citations
26
mBio, Journal Year: 2023, Volume and Issue: 14(1)
Published: Jan. 10, 2023
Acinetobacter baumannii is an increasing important nosocomial pathogen that difficult to combat due its ability survive in harsh environments and the emergence of isolates are resistant multiple antibiotics. A better understanding mechanism underlying toughness A. may identify Achilles’ heel, which will facilitate development novel preventive treatment measures.
Language: Английский
Citations
16
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
Autophagy, Journal Year: 2024, Volume and Issue: 20(9), P. 1968 - 1983
Published: May 31, 2024
Many bacterial pathogens have evolved effective strategies to interfere with the ubiquitination network evade clearance by innate immune system. Here, we report that OTUB1, one of most abundant deubiquitinases (DUBs) in mammalian cells, is subjected both canonical and noncanonical during Legionella pneumophila infection. The effectors SidC SdcA catalyze OTUB1 at multiple lysine residues, resulting its association a Legionella-containing vacuole. Lysine promotes interactions between DEPTOR, an inhibitor MTORC1 pathway, thus suppressing signaling. inhibition leads suppression host protein synthesis promotion macroautophagy/autophagy L. In addition, members SidE family (SidEs) induce phosphoribosyl (PR)-linked Ser16 Ser18 block DUB activity. levels serine are further regulated function antagonize activities SidC, SidEs, including Lem27, DupA, DupB, SidJ SdjA. Our study reveals effectors-mediated complicated mechanism regulating activity DUB.
Language: Английский
Citations
6
mBio, Journal Year: 2022, Volume and Issue: 13(3)
Published: April 21, 2022
Blocking host cell death is an important virulence strategy employed by many bacterial pathogens. We recently reported that Shigella flexneri inhibits pyroptosis delivering a type III secretion system (T3SS) effector OspC3 catalyzes novel arginine ADP-riboxanation modification on caspase-4/11. Here, we investigated the homologue CopC from Chromobacterium violaceum, opportunistic but sometimes deadly pathogen. bears same ADP-riboxanase activity as OspC3, with different substrate specificity. Through proteomic analysis, first identified calmodulin (CaM) binding partner of CopC. The analyses additionally revealed preferably modifies apoptotic caspases including caspase-7, -8 and -9. This results in suppression both extrinsic intrinsic apoptosis programs C. violaceum-infected cells. Biochemical reconstitution showed requires to CaM, specifically calcium-free state, achieve efficient caspases. determined crystal structure CaM-CopC-CASP7 ternary complex, which illustrates caspase recognition mechanism unique CaM-binding mode Structure-directed mutagenesis validated functional significance CaM for stimulating its substrates. adopts ADP-ribosyltransferase-like fold His-Phe-Glu catalytic triad, featuring two acidic residues critical site-specific ADP-riboxanation. Our study expands deepens our understanding OspC family effectors. IMPORTANCE Programmed suicidal defense eukaryotes combat pathogen infection. In evolutionary arms race host, bacteria are endowed ingenious tactics block facilitate their replication. report violaceum ADP-riboxanates caspase-7/8/9, enabled interacting factor calmodulin, apoptosis, illustrating sophisticated adopted counteract defense.
Language: Английский
Citations
21
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