The Coxiella burnetii T4SS effector protein AnkG hijacks the 7SK small nuclear ribonucleoprotein complex for reprogramming host cell transcription

Cordsmeier, Arne; Rinkel, Sven; Jeninga, Myriam D.; Schulze-Luehrmann, Jan; Ölke, Martha; Schmid, Benedikt; Hasler, Daniele; Meister, Gunter; Häcker, Georg; Petter, Michaela; Beare, Paul A.; Lührmann, Anja

doi:10.1371/journal.ppat.1010266

Cited by 13 publications

(12 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Future studies will be needed to further elucidate the interaction between CBU1314 and PAF1C and its possible role in modulating host transcription and the immune response. Intriguingly, it was recently shown that the C. burnetii effector AnkG interacts with the host factors DDX21 and 7SK snRNP complex, which are involved in host transcription (Cordsmeier et al, 2022). Thus, C. burnetii may employ multiple effectors that interact with host transcriptional machinery to modulate gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…While the functions of most effectors are still unknown, some effectors have been found to suppress innate immune responses. C. burnetii has four effectors (AnkG, CaeA, CaeB, IcaA) that suppress cell death pathways (Bisle et al, 2016; Cordsmeier et al, 2022; Cunha et al, 2015; Klingenbeck, Eckart, Berens, & Lührmann, 2013; Lührmann, Nogueira, Carey, & Roy, 2010), three effectors (CBU0885, CBU1676, CBU0388) that modulate the Cell Wall Integrity MAPK pathway in yeast (Lifshitz et al, 2014), and two recently discovered effectors (NopA and CinF) that suppress NF-κB signaling in human cells (Burette et al, 2020; Y. Zhang et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Fischer

Boyer

Bradley

et al. 2022

Preprint

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Fischer

Boyer

Bradley

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The eukaryotic type Ank domain in this protein family might have a role in host-cell attachment and allows the interaction of bacteria with a spectrum of host cell proteins and thus are particularly important in the pathogenic process (Batrukova, Betin, Rubtsov, et al . 2000; Cordsmeier, Rinkel, Jeninga, et al . 2022; Pechstein, Schulze-Luehrmann, Bisle, et al .…”

Section: Discussionmentioning

confidence: 99%

“…AnkG, AnkD and AnkK are ankyrin repeat-containing effector proteins in Cb (Seshadri, Paulsen, Eisen, et al 2003). The eukaryotic type Ank domain in this protein family might have a role in host-cell attachment and allows the interaction of bacteria with a spectrum of host cell proteins and thus are particularly important in the pathogenic process (Batrukova, Betin, Rubtsov, et al 2000;Cordsmeier, Rinkel, Jeninga, et al 2022;Pechstein, Schulze-Luehrmann, Bisle, et al 2020;Voth, Howe, Beare, et al 2009). AnkD has both eukaryotic like domain and F-box domain, but the function is not yet clear (Voth, Howe, Beare, et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptomics and Genomics from Continuous Axenic Media Growth IdentifiesCoxiella burnetiiIntracellular Survival Strategies

Yadav

Brewer

Elshahed

et al. 2023

Preprint

View full text Add to dashboard Cite

Coxiella burnetii (Cb) is an obligate intracellular pathogen in nature and the causative agent of acute Q fever as well as chronic diseases. In an effort to identify genes and proteins crucial to their normal intracellular growth lifestyle, we applied a Reverse evolution approach where the avirulent Nine Mile Phase II strain of Cb was grown for 67 passages in chemically defined ACCM-D media and gene expression patterns and genome integrity from various passages was compared to passage number one following intracellular growth. Transcriptomic analysis identified a marked downregulation of the structural components of the type 4B secretion system (T4BSS), the general secretory (sec) pathway, as well as 14 out of 118 previously identified genes encoding effector proteins. Additional downregulated pathogenicity determinants genes included several chaperones, LPS, and peptidoglycan biosynthesis. A general marked downregulation of central metabolic pathways was also observed, which was balanced by a marked upregulation of genes encoding transporters. This pattern reflected the richness of the media and diminishing anabolic and ATP-generation needs. Finally, genomic sequencing and comparative genomic analysis demonstrated an extremely low level of mutation across passages, despite the observed Cb gene expression changes following acclimation to axenic media.

show abstract

“…Notably, the C . burnetii T4SS effector AnkG inhibits host cell apoptosis by interacting with the host proteins p32, importin-α1 and RNA helicase 21 [ 7 , 8 ]. In addition to AnkG, the effectors CaeA and CaeB prevent mitochondrial-dependent (intrinsic) apoptosis [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Wang

et al. 2022

PLoS Pathog

View full text Add to dashboard Cite

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

show abstract

The Coxiella burnetii T4SS effector protein AnkG hijacks the 7SK small nuclear ribonucleoprotein complex for reprogramming host cell transcription

Cited by 13 publications

References 76 publications

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

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

Comparative Transcriptomics and Genomics from Continuous Axenic Media Growth IdentifiesCoxiella burnetiiIntracellular Survival Strategies

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

Contact Info

Product

Resources

About