Leishmania donovani Exploits Myeloid Cell Leukemia 1(MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Leishmania donovani Exploits Myeloid Cell Leukemia 1(MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis
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| Creator |
Giri, Jayeeta
Srivastav, Supriya Bose, Moumita Palit, Shreyasi Gupta, Purnima Ukil, Anindita |
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| Subject |
Infectious Diseases and Immunology
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| 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
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| Publisher |
American Society for Biochemistry and Molecular Biology
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| Date |
2016
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| 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. |
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| Relation |
http://dx.doi.org/10.1074/jbc.M115.672873
http://www.eprints.iicb.res.in/2476/ |
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