Reverting the mode of action of the mitochondrial FOF1-ATPase by Legionella pneumophila preserves its replication niche
| Autor: | Tobias Sahr, Platon L, Dramé M, Pedro Escoll, Carmen Buchrieser, Christophe Rusniok, Silke Schmidt |
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| Přispěvatelé: | Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), Université de Paris (UP), Collège doctoral [Sorbonne universités], Sorbonne Université (SU), This research was funded by the Institut Pasteur, DARRI - Institut Carnot - Microbe et santé (grant number INNOV-SP10-19) to PE, the Agence National de Recherche (grant number ANR-10-LABX- 62-IBEID) and the Fondation de la Recherché Médicale (FRM) (grant number EQU201903007847) to CB, and the Région Ile-de-France (program DIM1Health) to PBI (part of FranceBioImaging, ANR-10-INSB-04-01). MD was supported by the Ecole Doctorale FIRE – 'Programme Bettencourt'. SS was supported by the Pasteur Paris-University (PPU) International PhD Program., We acknowledge C.B.’s, P. Glaser’s lab members and F. Stavru at Institut Pasteur for fruitful discussions. We thank N. Aulner, A. Danckaert, Photonic BioImaging (PBI) UTechS and M. Hassan, Center for Translational Science (CRT) at Institut Pasteur, for support, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mémoires - Université de Montpellier - Faculté des sciences (UM FS), Faculté des sciences de Paris, Université de Paris (1896-1970), Collège Doctoral, This research was funded by the Institut Pasteur, DARRI-Institut Carnot-Microbe et santé (grant number INNOV-SP10-19) to PE, the Agence National de Recherche (grant number ANR-10-LABX-62-IBEID to CB and ANR-21-CE15-0038-01 to PE), the Fondation de la Recherché Médicale (FRM) (grant number EQU201903007847) to CB, and the Région Ile-de-France (program DIM1Health) to PBI (part of FranceBioImaging, ANR-10-INSB-04–01). MD was supported by the Ecole Doctorale FIRE – 'Programme Bettencourt.' SS was supported by the Pasteur Paris-University (PPU) International PhD Program., We acknowledge CB’s, P Glaser’s lab members, and F Stavru at Institut Pasteur for fruitful discussions. We specially thank Daniel Schator for help and discussions regarding HEK-293 infection and transfec- tion. We thank N Aulner, A Danckaert, Photonic BioImaging (PBI) UTechS and M Hassan, Center for Translational Science (CRT) at Institut Pasteur, for support., ANR-21-CE15-0038,MITOBAC,Interactions Métaboliques Hôte-Pathogène: Comment des Bactéries Intracellulaires détournent l'OXPHOS Mitochondriale pendant l'infection(2021), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
QH301-705.5 MESH: Mitochondria Science infectious disease FOF1-ATPase Oxidative phosphorylation [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Legionella pneumophila MESH: Proton-Translocating ATPases 03 medical and health sciences 0302 clinical medicine mitochondrial membrane potential MESH: Adenosine Triphosphate Biology (General) MESH: Bacterial Proteins MESH: Type IV Secretion Systems 030304 developmental biology Membrane potential 0303 health sciences Effector microbiology MESH: Mitochondrial Proteins Metabolism Microphthalmia-associated transcription factor biology.organism_classification MESH: Legionella pneumophila OXPHOS 3. Good health Cell biology macrophages mitochondria cell death Medicine Reprogramming 030217 neurology & neurosurgery |
| Zdroj: | eLife eLife, 2021, 10, ⟨10.7554/eLife.71978⟩ eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| Popis: | Legionella pneumophila, the causative agent of Legionnaires’ disease, a severe pneumonia, injects via a type-IV-secretion-system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δψm) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial FOF1-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δψm, preserves mitochondrial polarization and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that LpSpl is partially involved in conserving the Δψm, but not LncP and MitF. The inhibition of the L. pneumophila-induced “reverse mode” of the FOF1-ATPase collapsed the Δψm and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δψm and showed delayed cell death. This direct manipulation of the mode of activity of the FOF1-ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection. |
| Databáze: | OpenAIRE |
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