title: Bcl-xLmediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages.
abstract: Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host Mϕ, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected Mϕ is dependent on the action of the cytosolic Receptor Interacting Protein Kinase 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphoma-extra large (Bcl-xL). RIPK3-deficient Mϕ are able to better control bacterial growth in vitro and in vivo. Mechanistically, cytosolic RIPK3 translocates to the mitochondria where it promotes necrosis and blocks caspase 8-activation and apoptosis via Bcl-xL. Furthermore, necrosis is associated with stabilization of hexokinase II on the mitochondria as well as cyclophilin D-dependent mitochondrial permeability transition. Collectively, these events upregulate the level of reactive oxygen species to induce necrosis. Thus, in Mtb-infected Mϕ, mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8-activation.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Department of Microbiology and Immunology, McGill International TB Centre, McGill University Health Centre, Meakins-Christie Laboratories, Montreal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Khan
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: H
authors.initials: H
authors.lastname: Gan
authors.affiliation: Department of Medicine, Department of Microbiology and Immunology, McGill International TB Centre, McGill University Health Centre, Meakins-Christie Laboratories, Montreal, Quebec, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Tzelepis
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Health Center, Keio University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Medicine, Department of Microbiology and Immunology, McGill International TB Centre, McGill University Health Centre, Meakins-Christie Laboratories, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Divangahi
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D000818:Animals; D058491:Bacterial Load; D053181:Caspase 8 / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D004195:Disease Models, Animal; D006593:Hexokinase; D006801:Humans; D008264:Macrophages / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000276:immunology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494812:Bcl2l1 protein, mouse; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D051020:bcl-X Protein; D006593:Hexokinase; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8; D021983:Cyclophilins