title: The role of Mcl-1 in S. aureus-induced cytoprotection of infected macrophages.
abstract: As a facultative intracellular pathogen, Staphylococcus aureus invades macrophages and then promotes the cytoprotection of infected cells thus stabilizing safe niche for silent persistence. This process occurs through the upregulation of crucial antiapoptotic genes, in particular, myeloid cell leukemia-1 (MCL-1). Here, we investigated the underlying mechanism and signal transduction pathways leading to increased MCL-1 expression in infected macrophages. Live S. aureus not only stimulated de novo synthesis of Mcl-1, but also prolonged the stability of this antiapoptotic protein. Consistent with this, we proved a crucial role of Mcl-1 in S. aureus-induced cytoprotection, since silencing of MCL1 by siRNA profoundly reversed the cytoprotection of infected cells leading to apoptosis. Increased MCL1 expression in infected cells was associated with enhanced NFκB activation and subsequent IL-6 secretion, since the inhibition of both NFκB and IL-6 signalling pathways abrogated Mcl-1 induction and cytoprotection. Finally, we confirmed our observation in vivo in murine model of septic arthritis showing the association between the severity of arthritis and Mcl-1 expression. Therefore, we propose that S. aureus is hijacking the Mcl-1-dependent inhibition of apoptosis to prevent the elimination of infected host cells, thus allowing the intracellular persistence of the pathogen, its dissemination by infected macrophages, and the progression of staphylococci diseases.
authors: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Ul. Gronostajowa 7, 30-387 Kraków, Poland. joanna.koziel@uj.edu.pl
authors: Joanna
authors: J
authors: Koziel
authors: Katarzyna
authors: K
authors: Kmiecik
authors: Daniela
authors: D
authors: Chmiest
authors: Katarzyna
authors: K
authors: Maresz
authors: Danuta
authors: D
authors: Mizgalska
authors: Agnieszka
authors: A
authors: Maciag-Gudowska
authors: Piotr
authors: P
authors: Mydel
authors: Jan
authors: J
authors: Potempa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013211:Staphylococcus aureus / Q000472:pathogenicity*
chemical_list: D015850:Interleukin-6; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2