A protein–protein interaction map reveals that the Coxiella burnetii effector CirB inhibits host proteasome activity

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(7), P. e1010660 - e1010660

Published: July 11, 2022

Coxiella burnetii is the etiological agent of zoonotic disease Q fever, which featured by its ability to replicate in acid vacuoles resembling lysosomal network. One key virulence determinant C. Dot/Icm system that transfers more than 150 effector proteins into host cells. These effectors function construct lysosome-like compartment permissive for bacterial replication, but functions most these remain elusive. In this study, we used an affinity tag purification mass spectrometry (AP-MS) approach generate a burnetii-human protein-protein interaction (PPI) map involving 53 and 3480 proteins. This PPI revealed CBU0425 (designated CirB) interacts with subunits 20S core proteasome. We found ectopically expressed CirB inhibits hydrolytic activity addition, overexpression caused dramatic inhibition proteasome cells, while knocking down expression alleviated such inhibitory effects. Moreover, showed region spans residues 91-120 binds subunit PSMB5 (beta 5). Finally, knockdown promotes virulence, highlighting importance modulation during course infection.

Language: Английский

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Interdisciplinary studies on Coxiella burnetii: From molecular to cellular, to host, to one health research

International Journal of Medical Microbiology, Journal Year: 2023, Volume and Issue: 313(6), P. 151590 - 151590

Published: Nov. 1, 2023

The Q-GAPS (Q fever GermAn interdisciplinary Program for reSearch) consortium was launched in 2017 as a German of more than 20 scientists with exceptional expertise, competence, and substantial knowledge the field Q pathogen Coxiella (C.) burnetii. C. burnetii exemplifies zoonotic challenges disease control prophylaxis human, animal, environmental settings One Health approach. An approach to studying is essential address unresolved questions about epidemiology, immunology, pathogenesis, surveillance, In five years, has provided new insights into pathogenicity interaction host defense mechanisms. also investigated vaccine efficacy application animal reservoirs identified expanded phenotypic genotypic characteristics their epidemiological significance. addition, conceptual principles controlling, surveilling, preventing infections were developed prepared specific target groups. All findings have been continuously integrated Web-based, interactive, freely accessible information platform (www.q-gaps.de), which contains guidelines support public health institutions controlling fever. this review, we will summarize our results show an example how provides better tools at national level.

Language: Английский

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Identification of a Coxiella burnetii outer membrane porin required for intracellular replication

Infection and Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

ABSTRACT Coxiella burnetii is a gram-negative, obligate intracellular pathogen that causes human Q fever. Within host cells, C. proliferates in spacious, acidic, lysosome-derived -containing vacuole (CCV) by process requires the Dot/Icm type IVB secretion system to deliver effectors manipulate cell functions. A previous transposon mutagenesis screen identified gene cbu0937 as being important for replication of . Here, function Cbu0937 was investigated. The ::Tn mutant had no detectable defect replicating axenic acidified citrate cysteine medium 2. Additionally, not restored co-infection cells with an isogenic wild-type strain Thus, has cell-intrinsic defect. Intracellular complementing trans plasmid encoding either untagged or epitope-tagged version Cbu0937. Analysis predicted structure protein using AlphaFold revealed high similarity between and several bacterial porins. Fractionation studies surface labeling producing functional indicated localization outer membrane. From these data, we conclude encodes porin plays essential role supporting replication, which likely involves acquisition metabolite CCV lumen.

Language: Английский

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Nuclear warfare: pathogen manipulation of the nuclear pore complex and nuclear functions

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

ABSTRACT Viruses and bacteria exploit the nuclear pore complex (NPC) host functions to bypass cellular barriers manipulate essential processes. frequently engage directly with NPC components, such as nucleoporins, enable genome import evade immune defenses. In contrast, bacterial pathogens rely on secreted effector proteins disrupt transport reprogram transcription. These strategies reflect a remarkable evolutionary convergence, both types of targeting promote infection. This minireview explores overlapping unique mechanisms by which hijack nucleus, shedding light their roles in disease potential avenues for therapeutic intervention.

Language: Английский

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Progress in 7SK ribonucleoprotein structural biology

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: March 27, 2023

The 7SK ribonucleoprotein (RNP) is a dynamic and multifunctional regulator of RNA Polymerase II (RNAPII) transcription in metazoa. Comprised the non-coding RNA, core proteins, numerous accessory most well-known RNP function sequestration inactivation positive elongation factor b (P-TEFb). More recently, has been shown to regulate RNAPII through P-TEFb-independent pathways. Due its fundamental role cellular function, dysregulation linked with human diseases including cancers, heart disease, developmental disorders, viral infection. Significant advances structural biology have improved our understanding assembly function. Here, we review progress basis folding, biogenesis, assembly.

Language: Английский

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Comprehensive genome sequence analysis of Ralstonia solanacearum gd-2, a phylotype I sequevar 15 strain collected from a tobacco bacterial phytopathogen

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: March 14, 2024

Introduction Plant bacterial wilt is an important worldwide disease caused by Ralstonia solanacearum which a complex of species. Methods In this study, we identified and sequenced the genome R. strain gd-2 isolated from tobacco. Results Strain was as species (RSSC) phylotype I sequevar 15 exhibited strong pathogenicity to The size 5.93 Mb, including chromosomes (3.83 Mb) megaplasmid (2.10 Mb). Gene prediction results showed that 3,434 1,640 genes were in plasmids, respectively. Comparative genomic analysis high conservation with ten highly similar genomes differences between other mainly located at positions GI12-GI14. 72 type III effectors (T3Es) RipAZ2 T3E specific compared eight strain. Discussion Our study provides new basis evidence for studying pathogenic mechanism .

Language: Английский

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Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress–induced cell death

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(36)

Published: Aug. 28, 2023

The causative agent of human Q fever, Coxiella burnetii, is highly adapted to infect alveolar macrophages by inhibiting a range host responses infection. Despite the clinical and biological importance this pathogen, challenges related genetic manipulation both C. burnetii have limited our knowledge mechanisms which subverts functions. Here, we used bacterium Legionella pneumophila perform comprehensive screen effectors that interfere with innate immune death using greater wax moth Galleria mellonella mouse bone marrow–derived macrophages. We identified MceF (Mitochondrial effector protein F), localizes mitochondria contributes cell survival. was shown enhance mitochondrial function, delay membrane damage, decrease ROS production induced rotenone. Mechanistically, recruits antioxidant Glutathione Peroxidase 4 (GPX4) mitochondria. protective functions were absent in primary lacking GPX4, while overexpression cells protected against oxidative stress–induced death. replication competent mammalian but higher mortality G. mellonella, indicating modulates response This study reveals an important strategy subvert macrophage immunity demonstrates modulation system viable promote success intracellular bacteria.

Language: Английский

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Cell death induction facilitates egress of Coxiella burnetii from infected host cells at late stages of infection

Molecular Microbiology, Journal Year: 2023, Volume and Issue: 121(3), P. 513 - 528

Published: Dec. 19, 2023

Intracellular bacteria have evolved mechanisms to invade host cells, establish an intracellular niche that allows survival and replication, produce progeny, exit the cell after completion of replication cycle infect new target cells. Bacteria their by (i) initiation apoptosis, (ii) lytic death, (iii) exocytosis. While bacterial egress is essential for spreading and, thus, pathogenesis, we currently lack information about obligate pathogen C. burnetii, causative agent zoonosis Q fever. Here, demonstrate burnetii inhibits apoptosis early during infection, but induces and/or increases at later stages infection. Only infection did observe egress, which depends on previously established large bacteria-filled vacuoles a functional intrinsic apoptotic cascade. The released are not enclosed membrane can replicate in In summary, our data argue non-synchronous way late Apoptosis-induction important other pathways most likely contribute.

Language: Английский

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A Coxiella burnetii effector interacts with the host PAF1 complex and suppresses the innate immune response

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: April 26, 2022

Abstract Intracellular bacteria such as the pathogen Coxiella burnetii inject effector proteins into host cell that promote productive infection. One common strategy of effectors is to suppress immune responses enable replication. The C. type IV secretion system translocates a large number cells collectively intracellular bacterial replication, but individual functions most these are poorly understood. In this study, we describe effector, CBU1314, localizes nucleus and inhibits NF-κB-, MAPK-, I IFN-dependent gene expression. Mechanistically, find CBU1314 interacts with PAF1 complex (PAF1C), central transcriptional regulates expression inflammatory genes in innate cells. Notably, promotes response various agonists Moreover, critical for restricting Overall, our findings uncover PAF1C target reveal new insight how pathogens subvert cell- intrinsic defenses. Significance often employ secreted modulate cellular processes survive intracellularly. study can provide valuable microbial pathogenesis biology. Here, multiple signaling pathways modulates response. This regulator transcription. Furthermore, show necessary maximal downstream receptors restricts replication during elucidates function evading provides role cell-intrinsic defense against pathogens.

Language: Английский

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Role of mitochondrial outer membrane permeabilization during bacterial infection

International review of cell and molecular biology, Journal Year: 2022, Volume and Issue: unknown, P. 83 - 127

Published: Nov. 14, 2022

Language: Английский

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