Zhao, XiaominKhan, NargisGan, HuixianTzelepis, FannyNishimura, TomoyasuPark, Seung-YeolDivangahi, MaziarRemold, Heinz2017-12-062017Zhao, Xiaomin, Nargis Khan, Huixian Gan, Fanny Tzelepis, Tomoyasu Nishimura, Seung-Yeol Park, Maziar Divangahi, and Heinz G. Remold. 2017. “Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages.” Mucosal immunology 10 (6): 1553-1568. doi:10.1038/mi.2017.12. http://dx.doi.org/10.1038/mi.2017.12.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492164Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host Mφ, which is essential for successful pathogenesis. Here we demonstrate that necrosis of Mtb-infected Mφ is dependent on the action of the cytosolic kinase Receptor Interacting Protein 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. 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 (MPT). These events up-regulate the level of reactive oxygen species (ROS) 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.en-USJournal Article2017-12-0610.1038/mi.2017.12