Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection

• Published in: The international journal of biochemistry & cell biology Vol. 55; pp. 196 - 208
• Main Authors: Mukherjee, Madhuchhanda, Basu Ball, Writoban, Das, Pijush K.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.2014
• Subjects: acidification; Activation; Animals; Blotting, Western; Cell Membrane - immunology; Cell Membrane - metabolism; Cells, Cultured; Cholesterol; Cholesterol - immunology; Cholesterol - metabolism; Circuits; Female; HMGCR; Host-Parasite Interactions - immunology; Humans; Hydroxymethylglutaryl CoA Reductases - genetics; Hydroxymethylglutaryl CoA Reductases - immunology; Hydroxymethylglutaryl CoA Reductases - metabolism; Ion Channels - genetics; Ion Channels - metabolism; Leishmania donovani; Leishmania donovani - immunology; Leishmania donovani - physiology; Leishmaniasis, Visceral - immunology; Leishmaniasis, Visceral - metabolism; Leishmaniasis, Visceral - parasitology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - parasitology; membrane fluidity; Membranes; Mice, Inbred BALB C; Mitochondria; Mitochondria - immunology; Mitochondria - metabolism; Mitochondria - parasitology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; neutralization; Oxidants - immunology; Oxidants - metabolism; Parasites; Pathogens; Phosphatidylinositol 3-Kinases - immunology; Phosphatidylinositol 3-Kinases - metabolism; plasma membrane; Proto-Oncogene Proteins c-akt - immunology; Proto-Oncogene Proteins c-akt - metabolism; reactive oxygen species; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference - immunology; Signal Transduction - immunology; src-Family Kinases - immunology; src-Family Kinases - metabolism; SREBP2; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - immunology; Sterol Regulatory Element Binding Protein 2 - metabolism; Survival; tau-protein kinase; transcription factors; Uncoupling Protein 2; Visceral leishmaniasis; bHLH-Zip; DAPI; HMGCR; ER; ORO; Cholesterol; Mitochondria; Visceral leishmaniasis; MβCD; UCP2; ROS; SREBP2; SCAP; PM; LDLr
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2014.08.019

•Leishmania phagocytosis activates SREBP2 circuit.•PM-ER fusion and membrane raft reorientation-mediated Lyn-PI3K/Akt pathway activation increase nuclear transport and stability of SREBP2.•SREBP2 regulates cholesterol biosynthesis, mitochondrial ROS generation and cytokine balance.•Leishmania targets a master transcriptional regulator SREBP2 to manipulate a multitude of host events facilitating its invasion and survival. Establishment of infection by an intracellular pathogen depends on successful internalization with a concomitant neutralization of host defense machinery. Leishmania donovani, an intramacrophage pathogen, targets host SREBP2, a critical transcription factor, to regulate macrophage plasma membrane cholesterol and mitochondrial reactive oxygen species generation, favoring parasite invasion and persistence. Leishmania infection triggered membrane-raft reorientation-dependent Lyn-PI3K/Akt pathway activation which in turn deactivated GSK3β to stabilize nuclear SREBP2. Moreover, cells perceiving less available intracellular cholesterol due to its sequestration at the plasma membrane resulted in the deregulation of the ER-residing SCAP-SREBP2-Insig circuit thereby assisting increased nuclear translocation of SREBP2. Both increased nuclear transport and stabilization of SREBP2 caused HMGCR-catalyzed cholesterol biosynthesis-mediated plasma membrane cholesterol enrichment leading to decreased membrane-fluidity and plausibly assisting delay in phagosomal acidification. Parasite survival ensuing entry was further ensured by SREBP2-dependent trasnscriptional up-regulation of UCP2, which suppressed mitochondrial ROS generation, one of the primary microbicidal molecules in macrophages recognized for its efficacy against Leishmania. Functional knock-down of SREBP2 both in vitro and in vivo was associated with reduction in macrophage plasma membrane cholesterol, increased ROS production and lower parasite survival. To our knowledge, this study, for the first time, reveals that Leishmania exploits macrophage cholesterol-dependent SREBP2 circuit to facilitate its entry and survival within the host.