The ever‐increasing necessity of mass spectrometry in dissecting protein post‐translational modifications catalyzed by bacterial effectors DOI Open Access
Jie Jin, Yi Yuan, Wei Xian

et al.

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

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms DOI Creative Commons
Jiaqi Fu, Siying Li, Hongxin Guan

et al.

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

9
The Legionella pneumophila Dot/Icm type IV secretion system and its effectors DOI
Daniel C. Lockwood, Himani Amin, Tiago R. D. Costa

et al.

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
Lysionotin Induces Ferroptosis to Suppress Development of Colorectal Cancer via Promoting Nrf2 Degradation DOI Creative Commons
Zhuo Gao, Junnan Jiang, Lijian Hou

et al.

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

25
Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain DOI Creative Commons
Zhengrui Zhang, Jiaqi Fu, J.G.M. Rack

et al.

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
Legionella pneumophila exploits the endo-lysosomal network for phagosome biogenesis by co-opting SUMOylated Rab7 DOI Creative Commons
Chuang Li, Jiaqi Fu, Shuai Shao

et al.

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
Reversible modification of mitochondrial ADP/ATP translocases by paired Legionella effector proteins DOI Creative Commons
Tomoko Kubori,

Junyup Lee,

Hyunmin Kim

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(23)

Published: June 2, 2022

Significance Mitochondria are organelles of the central metabolism that produce ATP and play fundamental roles in eukaryotic cell function thereby become targets for pathogenic bacteria to manipulate. We found intracellular bacterial pathogen, Legionella pneumophila , mitochondrial ADP/ATP translocases (ANTs), which is linked synthesis. This achieved by a pair effector proteins, Lpg0080 Lpg0081, have opposing enzymatic activities as an ADP ribosyltransferase (ART) ribosylhydrolase (ARH), respectively, coordinately regulating chemical modification ANTs upon infection. Our structural analyses indicate Lpg0081 ARH with noncanonical macrodomain, whose folding topology distinct from canonical macrodomain known eukaryotic, archaeal, proteins.

Language: Английский

Citations

17
For Better or Worse: Type I Interferon Responses in Bacterial Infection DOI Creative Commons
Aihong Xia,

Xin Li,

Changjing Zhao

et al.

Pathogens, Journal Year: 2025, Volume and Issue: 14(3), P. 229 - 229

Published: Feb. 26, 2025

Type I interferons (IFNs) are pleiotropic cytokines, primarily comprising IFN-α and IFN-β, their effect in host defense against viral infection has been extensively studied well-established. However, bacterial infection, the role of type IFNs is more complex, exhibiting multifaceted effects that depend on several factors, such as pathogen species, specific cell populations, routes infection. In this review, we summarize research progress interferon responses triggered by bacteria immune regulation function order to better understand provide insights for adjuvant therapies tailored treat infections.

Language: Английский

Citations

0
Comprehensive analysis of the type VI secretion system in Neisseria: identification, distribution, and evolutionary insights DOI Creative Commons

Tingting Dong,

Wenjing Yi,

Meng Zhang

et al.

BMC Genomics, Journal Year: 2025, Volume and Issue: 26(1)

Published: May 2, 2025

Language: Английский

Citations

0
Modulation of host ATP levels by secreted bacterial effectors DOI Creative Commons

Chunlin He,

Chuang Li, Yao Liu

et al.

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
Small molecule communication of Legionella : the ins and outs of autoinducer and nitric oxide signaling DOI

Sarah Michaelis,

Laura Gomez‐Valero, Tong Chen

et al.

Microbiology and Molecular Biology Reviews, Journal Year: 2024, Volume and Issue: 88(3)

Published: Aug. 20, 2024

SUMMARY Legionella pneumophila is a Gram-negative environmental bacterium, which survives in planktonic form, colonizes biofilms, and infects protozoa. Upon inhalation of -contaminated aerosols, the opportunistic pathogen replicates within destroys alveolar macrophages, thereby causing severe pneumonia termed Legionnaires’ disease. bacteria employ low molecular weight organic compounds as well inorganic gas nitric oxide (NO) for cell-cell communication. L. produces, secretes, detects α-hydroxyketone compound autoinducer-1 (LAI-1, 3-hydroxypentadecane-4-one). LAI-1 secreted by outer membrane vesicles not only promotes communication among but also triggers responses from eukaryotic cells. NO through three different receptors, signaling volatile molecule translates into fluctuations intracellular second messenger cyclic-di-guanylate monophosphate. The pathways are linked via pleiotropic transcription factor LvbR. In this review, we summarize current knowledge about inter-bacterial inter-kingdom species.

Language: Английский

Citations

3