title: Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis.
abstract: 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 the mRNA and 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-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 the macrophage anti-apoptotic protein MCL-1 to prevent BAK-mediated mitochondria-dependent apoptosis thereby protecting its niche, which is essential for disease progression.
authors.affiliation: From the Department of Biochemistry, University of Calcutta, Kolkata and.
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Giri
authors.affiliation: the Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Supriya
authors.initials: S
authors.lastname: Srivastav
authors.affiliation: From the Department of Biochemistry, University of Calcutta, Kolkata and.
authors.forename: Moumita
authors.initials: M
authors.lastname: Basu
authors.affiliation: the Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Shreyasi
authors.initials: S
authors.lastname: Palit
authors.affiliation: From the Department of Biochemistry, University of Calcutta, Kolkata and.
authors.forename: Purnima
authors.initials: P
authors.lastname: Gupta
authors.affiliation: From the Department of Biochemistry, University of Calcutta, Kolkata and aninditau@yahoo.com.
authors.forename: Anindita
authors.initials: A
authors.lastname: Ukil
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006790:Host-Parasite Interactions / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology / Q000473:pathology
chemical_list: D000977:Antiparasitic Agents; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D003609:Dactinomycin
keywords: B-cell lymphoma 2 (Bcl-2) family; Leishmania; apoptosis; cytochrome c; macrophage