Leishmania donovani exploits myeloid cell leukemia 1 (MCL-1) protein to prevent mitochondria dependent host cell apoptosis [Cell Biology]

December 15th, 2015 by Giri, J., Srivastav, S., Basu, M., Palit, S., Gupta, P., Ukil, A.

Apoptosis is one of the mechanisms used by host cells to get rid of unwanted intracellular organisms, and often found to be subverted by pathogens through use of host anti-apoptotic proteins. In the present study, with the help of in vitro and in vivo approaches, we documented that the macrophage anti-apoptotic protein myeloid cell leukemia 1 (MCL-1) is exploited by the intra-macrophage parasite Leishmania donovani to protect their "home" from actinomycin D-induced mitochondria-dependent apoptosis. Amongst all the anti apoptotic BCL-2 family members, infection preferentially up-regulated expression of MCL-1 at both the mRNA and protein levels, and compared to infected control, MCL-1 silenced infected macrophages documented enhanced caspase activity and increased apoptosis when subjected to actinomycin D treatment. Phosphorylation kinetics and ChIP assay demonstrated that infection induced MCL-1 expression was regulated by the transcription factor CREB and silencing of CREB resulted in reduced expression of MCL-1 and increased apoptosis. During infection, MCL-1 was found to be localized in mitochondria and this was significantly reduced in Tom70 silenced macrophages, suggesting the active role of TOM70 in MCL-1 transport. In the mitochondria, MCL-1 interacts with the major pro-apoptotic protein BAK and prevents BAK-BAK homo-oligomer formation thereby preventing cytochrome c release mediated mitochondrial dysfunction. Silencing of MCL-1 in the spleen of infected mice showed decreased parasite burden and increased induction of splenocyte apoptosis. Collectively our results showed that L. donovani exploited macrophage anti-apoptotic protein MCL-1 to prevent BAK mediated mitochondria dependent apoptosis thereby protecting its niche, which is essential for disease progression.