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Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages.

ABSTRACT: Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host M?, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected M? 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 M? 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 M?, mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8-activation.

SUBMITTER: Zhao X 

PROVIDER: S-EPMC5638669 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Bcl-x<sub>L</sub> mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages.

Zhao X X   Khan N N   Gan H H   Tzelepis F F   Nishimura T T   Park S-Y SY   Divangahi M M   Remold H G HG  

Mucosal immunology 20170412 6

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-x<sub>L</sub>). RIPK3-deficient Mϕ are able to better control bacterial growth in vitro and in vivo. Mechanistically, cytosolic RIPK3 tran  ...[more]

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