title: The inhibition of the apoptosis pathway by the Coxiella burnetii effector protein CaeA requires the EK repetition motif, but is independent of survivin.
abstract: ABSRTACT Coxiella burnetii is an obligate intracellular bacterium that causes Query (Q) fever, a zoonotic disease. It requires a functional type IV secretion system (T4SS) which translocate bacterial effector proteins into the host cell cytoplasm and thereby facilitates bacterial replication. To date, more than 130 effector proteins have been identified, but their functions remain largely unknown. Recently, we demonstrated that one of these proteins, CaeA (CBU1524) localized to the host cell nucleus and inhibited intrinsic apoptosis of HEK293 or CHO cells. In the present study we addressed the question whether CaeA also affects the extrinsic apoptosis pathway. Ectopic expression of CaeA reduced extrinsic apoptosis and prevented the cleavage of the executioner caspase 7, but did not impair the activation of initiator caspase 9. CaeA expression resulted in an up-regulation of survivin (an inhibitor of activated caspases), which, however, was not causal for the anti-apoptotic effect of CaeA. Comparing the sequence of CaeA from 25 different C. burnetii isolates we identified an EK (glutamic acid/ lysine) repetition motif as a site of high genetic variability. The EK motif of CaeA was essential for the anti-apoptotic activity of CaeA. From these data, we conclude that the C. burnetii effector protein CaeA interferes with the intrinsic and extrinsic apoptosis pathway. The process requires the EK repetition motif of CaeA, but is independent of the upregulated expression of survivin.
authors.affiliation: a Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bisle
authors.affiliation: a Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Klingenbeck
authors.affiliation: b Bioinformatics Unit, Department of Infectious Diseases, National Institute of Health , Lisbon , Portugal.
authors.forename: Vítor
authors.initials: V
authors.lastname: Borges
authors.affiliation: c Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis , Jena , Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Sobotta
authors.affiliation: a Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schulze-Luehrmann
authors.affiliation: c Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis , Jena , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Menge
authors.affiliation: d Institut für Hygiene und Infektionskrankheiten der Tiere, Justus Liebig Universität Gießen , Gießen , Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Heydel
authors.affiliation: b Bioinformatics Unit, Department of Infectious Diseases, National Institute of Health , Lisbon , Portugal.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Gomes
authors.affiliation: a Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Lührmann
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D016997:Coxiella burnetii / Q000737:chemistry* / Q000235:genetics / Q000472:pathogenicity*; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D000077022:Survivin; D000069319:Type IV Secretion Systems / Q000235:genetics / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D001426:Bacterial Proteins; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D000069319:Type IV Secretion Systems; D053179:Caspase 7; D053453:Caspase 9
keywords: Coxiella burnetii; apoptosis; bacterial pathogenesis; surviving; type IV secretion system