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Leishmania donovani Exploits Myeloid Cell Leukemia 1(MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

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Title Leishmania donovani Exploits Myeloid Cell Leukemia 1(MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis
 
Creator Giri, Jayeeta
Srivastav, Supriya
Bose, Moumita
Palit, Shreyasi
Gupta, Purnima
Ukil, Anindita
 
Subject Infectious Diseases and Immunology
 
Description Apoptosis is one of the mechanisms used by host cells to
remove 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. Among all the anti-apoptotic BCL-2 family members, infection preferentially up-regulated expression of MCL-1 at both themRNAand protein levels and compared with 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 transcription factor CREB(cAMP-response element-binding protein) 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-silencedMCL-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 the macrophage anti-apoptotic protein MCL-1 to prevent BAK-mediated mitochondria-dependent apoptosis thereby protecting its niche, which is essential for disease progression.
macrophages, suggesting the active role of TOM70 in
 
Publisher American Society for Biochemistry and Molecular Biology
 
Date 2016
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2476/1/JOURNAL_OF_BIOLOGICAL_CHEMISTRYVOLUME_291%E2%80%A2NUMBER_7%E2%80%A2FEBRUARY_12%2C_2016.pdf
Giri, Jayeeta and Srivastav, Supriya and Bose, Moumita and Palit, Shreyasi and Gupta, Purnima and Ukil, Anindita (2016) Leishmania donovani Exploits Myeloid Cell Leukemia 1(MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis. The Journal of Biological Chemistry, 291 (7). pp. 3496-3507.
 
Relation http://dx.doi.org/10.1074/jbc.M115.672873
http://www.eprints.iicb.res.in/2476/