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

Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host M phi, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected M phi is dependent on the action of the cytosolic Receptor Interacting Protein Kinase 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphomaextra-large (Bcl-x(L)). RIPK3-deficient M phi 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-x(L). 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 phi, mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8-activation.