title: Leishmania donovani activates uncoupling protein 2 transcription to suppress mitochondrial oxidative burst through differential modulation of SREBP2, Sp1 and USF1 transcription factors.
abstract: In order to reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of cellular as well as mitochondrial reactive oxygen species (ROS), which is a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling protein 2 (UCP2) is strongly induced in Leishmania infection, both at mRNA and protein levels, to suppress the mitochondrial ROS generation. In the present study we have demonstrated that Leishmania donovani infection is associated with strong up-regulation of UCP2 at mRNA level which is the determining factor for its protein level upregulation. The transcriptional activation of UCP2 was mediated by increased nuclear translocation and DNA binding of sterol regulatory element binding protein 2 (SREBP2) and specificity protein 1 (Sp1) transcription factors with concomitant decrease of both the nuclear content and the promoter occupancy of upstream stimulatory factor 1 (USF1). siRNA-mediated silencing of SREBP2 or Sp1 was associated with decreased UCP2 expression in infected macrophages. In contrast, downregulation of USF1 resulted in activated transcription of UCP2. L. donovani infection resulted in degradation of USF1 thereby facilitating SREBP2 binding which in turn assisted in the association of Sp1 with the promoter ultimately culminating in elevated transcription of UCP2.
authors.affiliation: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Writoban Basu
authors.initials: WB
authors.lastname: Ball
authors.affiliation: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Mukherjee
authors.affiliation: 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: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India. Electronic address: pijushdas@iicb.res.in.
authors.forename: Pijush K
authors.initials: PK
authors.lastname: Das
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007893:Leishmania donovani / Q000378:metabolism*; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016897:Respiratory Burst / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D000071246:Uncoupling Protein 2; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse
keywords: Specificity protein 1; Sterol regulatory element binding protein 2; Uncoupling protein 2; Upstream stimulatory factor 1; Visceral leishmaniasis