Leishmania donovani activates uncoupling protein 2 transcription to suppress mitochondrial oxidative burst through differential modulation of SREBP2, Sp1 and USF1 transcription factors

• Published in: The international journal of biochemistry & cell biology Vol. 48; pp. 66 - 76
• Main Authors: Basu Ball, Writoban, Mukherjee, Madhuchhanda, Srivastav, Supriya, Das, Pijush K.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.03.2014
• Subjects: Activation; Animals; Binding; binding proteins; Cell Differentiation - physiology; Cell Line; Cellular; Degradation; DNA; Gene expression; Ion Channels - biosynthesis; Ion Channels - genetics; Ion Channels - metabolism; Leishmania donovani; Leishmania donovani - metabolism; Leishmaniasis, Visceral - genetics; Leishmaniasis, Visceral - metabolism; Leishmaniasis, Visceral - parasitology; Macrophages; Macrophages - metabolism; Macrophages - parasitology; messenger RNA; Mice; Mice, Inbred BALB C; mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - biosynthesis; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Modulation; parasites; pathogens; protein content; Proteins; reactive oxygen species; Respiratory Burst - physiology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Specificity protein 1; Sterol regulatory element binding protein 2; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - metabolism; sterols; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Transfection; Uncoupling Protein 2; Upstream stimulatory factor 1; Upstream Stimulatory Factors - genetics; Upstream Stimulatory Factors - metabolism; Visceral leishmaniasis; NF-Y; SREBP; Specificity protein 1; AP; CREB; PPAR; Uncoupling protein 2; Upstream stimulatory factor 1; Sp1; TSS; Visceral leishmaniasis; VL; DHR 123; ROS; UCP2; Sterol regulatory element binding protein 2; GRE; LDU
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2014.01.004

•Reactive oxygen species (ROS) is a fundamental microbicidal molecule of macrophages.•Uncoupling protein 2 (UCP2), a negative regulator of mitochondrial ROS generation, was upregulated in Leishmania donovani infection.•SREBP2, Sp1 and USF1 co-ordinated the expression of UCP2 during infection.•Ubiquitination-mediated degradation of USF1 plays a crucial role in transcriptional upregulation of UCP2.•This study reveals novel host manipulating pathways employed by the parasite along with the underlying molecular mechanisms involved. 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.