The anti-apoptotic Coxiella burnetii effector protein AnkG is a strain specific virulence factor

Schäfer, Walter; Schmidt, Teresa; Cordsmeier, Arne; Borges, Vítor; Beare, Paul A.; Pechstein, Julian; Schulze-Luehrmann, Jan; Holzinger, Jonas; Wagner, Nicole D.; Berens, Christian; Heydel, Carsten; Gomes, João Paulo; Lührmann, Anja

doi:10.1038/s41598-020-72340-9

Cited by 17 publications

(28 citation statements)

References 60 publications

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“…After confirming efficient elimination of CDK9 by THAL ( Fig 8B ), we analyzed whether the presence or absence of CDK9 influences the activity of GFP-AnkG 1-28 . While GFP-AnkG 1-28 expression protected the cells from staurosporine-induced apoptosis, as shown before [ 17 ], it did not protect from THAL-induced apoptosis ( Fig 8C ). Treatment with both, staurosporine and THAL, increased the rate of apoptotic cells.…”

Section: Resultssupporting

confidence: 83%

“…To get a first impression whether the interaction of AnkG with DDX21 might be important for the anti-apoptotic activity of AnkG, we asked which parts of AnkG might interact with DDX21. We have previously shown that the N-terminal region of AnkG, comprising amino acids 1–28, is necessary and sufficient for anti-apoptotic activity and exclusively localizes in the host cell nucleus, while the region from amino acids 70–338 did not prevent cell death and has a cytoplasmic localization [ 14 , 15 , 17 ]. As shown in Fig 2B , HA-tagged DDX21 was bound by GFP-AnkG 1-28 and GFP-AnkG 1-69 , but not by GFP-AnkG 70-338 , indicating that DDX21 binds to the anti-apoptotic region of AnkG.…”

Section: Resultsmentioning

confidence: 99%

“…AnkG´s activity inside the host cell is controlled by intracellular trafficking and depends on nuclear localization [ 14 , 16 ]. The first 28 amino acids are necessary and sufficient for its anti-apoptotic activity ( Fig 1 ) [ 17 ]. However, how AnkG alters nuclear activity to prevent host cell death was an open question [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Inhibition of host cell apoptosis is crucial for survival and replication of several intracellular bacterial pathogens. To interfere with apoptotic pathways, some pathogens use specialized secretion systems to inject bacterial effector proteins into the host cell cytosol. One of these pathogens is the obligate intracellular bacterium Coxiella burnetii, the etiological agent of the zoonotic disease Q fever. In this study, we analyzed the molecular activity of the anti-apoptotic T4SS effector protein AnkG (CBU0781) to understand how C. burnetii manipulates host cell viability. We demonstrate by co- and RNA-immunoprecipitation that AnkG binds to the host cell DExD box RNA helicase 21 (DDX21) as well as to the host cell 7SK small nuclear ribonucleoprotein (7SK snRNP) complex, an important regulator of the positive transcription elongation factor b (P-TEFb). The co-immunoprecipitation of AnkG with DDX21 is probably mediated by salt bridges and is independent of AnkG-7SK snRNP binding, and vice versa. It is known that DDX21 facilitates the release of P-TEFb from the 7SK snRNP complex. Consistent with the documented function of released P-TEFb in RNA Pol II pause release, RNA sequencing experiments confirmed AnkG-mediated transcriptional reprogramming and showed that expression of genes involved in apoptosis, trafficking, and transcription are influenced by AnkG. Importantly, DDX21 and P-TEFb are both essential for AnkG-mediated inhibition of host cell apoptosis, emphasizing the significance of the interaction of AnkG with both, the DDX21 protein and the 7SK RNA. In line with a critical function of AnkG in pathogenesis, the AnkG deletion C. burnetii strain was severely affected in its ability to inhibit host cell apoptosis and to generate a replicative C. burnetii-containing vacuole. In conclusion, the interference with the activity of regulatory host cell RNAs mediated by a bacterial effector protein represent a novel mechanism through which C. burnetii modulates host cell transcription, thereby enhancing permissiveness to bacterial infection.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…It has been seen that the amino terminal 1–69 region codify a domain that is both necessary and sufficient to interact with p32 and to inhibit the apoptosis, whereas truncated variants are not able to block apoptosis. Moreover, to prevent pathogen-induced cell death, AnkG needs to be localized in the nucleus ( Eckart et al., 2014 ; Schäfer et al., 2017 ; Schäfer et al., 2020 ).…”

Section: Apoptosis and Inflammasome In Coxiella Burnetii Infectionsmentioning

confidence: 99%

Recent Advances on the Innate Immune Response to Coxiella burnetii

Sireci¹,

Badami²,

Liberto³

et al. 2021

Front. Cell. Infect. Microbiol.

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Coxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of a worldwide zoonosis known as Q fever. The pathogen invades monocytes and macrophages, replicating within acidic phagolysosomes and evading host defenses through different immune evasion strategies that are mainly associated with the structure of its lipopolysaccharide. The main transmission routes are aerosols and ingestion of fomites from infected animals. The innate immune system provides the first host defense against the microorganism, and it is crucial to direct the infection towards a self-limiting respiratory disease or the chronic form. This review reports the advances in understanding the mechanisms of innate immunity acting during C. burnetii infection and the strategies that pathogen put in place to infect the host cells and to modify the expression of specific host cell genes in order to subvert cellular processes. The mechanisms through which different cell types with different genetic backgrounds are differently susceptible to C. burnetii intracellular growth are discussed. The subsets of cytokines induced following C. burnetii infection as well as the pathogen influence on an inflammasome-mediated response are also described. Finally, we discuss the use of animal experimental systems for studying the innate immune response against C. burnetii and discovering novel methods for prevention and treatment of disease in humans and livestock.

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“…CvpB binds to phosphatidylinositol 3-phosphate to enhance association of the autophagosomal components to the CCV ( Martinez et al., 2016 ). Another effector, AnkG plays a key role in anti-apoptosis, which is distinct from maturation of the CCV, though it is important in progression of disease in a Galleria mellonella infection model ( Schafer et al., 2020 ). NopA is injected into host cells and impacts the innate immune response to Coxiella infection, but does not impact trafficking of this pathogen to a replicative CCV ( Burette et al., 2020 ).…”

Section: The Lysosomal-like Coxiella -Containing Vacuolementioning

confidence: 99%

Idiosyncratic Biogenesis of Intracellular Pathogens-Containing Vacuoles

Vaughn

Kwaik

2021

Front. Cell. Infect. Microbiol.

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While most bacterial species taken up by macrophages are degraded through processing of the bacteria-containing vacuole through the endosomal-lysosomal degradation pathway, intravacuolar pathogens have evolved to evade degradation through the endosomal-lysosomal pathway. All intra-vacuolar pathogens possess specialized secretion systems (T3SS-T7SS) that inject effector proteins into the host cell cytosol to modulate myriad of host cell processes and remodel their vacuoles into proliferative niches. Although intravacuolar pathogens utilize similar secretion systems to interfere with their vacuole biogenesis, each pathogen has evolved a unique toolbox of protein effectors injected into the host cell to interact with, and modulate, distinct host cell targets. Thus, intravacuolar pathogens have evolved clear idiosyncrasies in their interference with their vacuole biogenesis to generate a unique intravacuolar niche suitable for their own proliferation. While there has been a quantum leap in our knowledge of modulation of phagosome biogenesis by intravacuolar pathogens, the detailed biochemical and cellular processes affected remain to be deciphered. Here we discuss how the intravacuolar bacterial pathogens Salmonella, Chlamydia, Mycobacteria, Legionella, Brucella, Coxiella, and Anaplasma utilize their unique set of effectors injected into the host cell to interfere with endocytic, exocytic, and ER-to-Golgi vesicle traffic. However, Coxiella is the main exception for a bacterial pathogen that proliferates within the hydrolytic lysosomal compartment, but its T4SS is essential for adaptation and proliferation within the lysosomal-like vacuole.

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The anti-apoptotic Coxiella burnetii effector protein AnkG is a strain specific virulence factor

Cited by 17 publications

References 60 publications

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

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

Recent Advances on the Innate Immune Response to Coxiella burnetii

Idiosyncratic Biogenesis of Intracellular Pathogens-Containing Vacuoles

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