title: Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection.
abstract: 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 transcriptional 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.
authors.affiliation: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Mukherjee
authors.affiliation: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Writoban
authors.initials: W
authors.lastname: Basu Ball
authors.affiliation: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India. Electronic address: pijushdas@iicb.res.in.
authors.forename: Pijush K
authors.initials: PK
authors.lastname: Das
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007893:Leishmania donovani / Q000276:immunology* / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071246:Uncoupling Protein 2; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D016877:Oxidants; D051782:Sterol Regulatory Element Binding Protein 2; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Cholesterol; HMGCR; Mitochondria; SREBP2; Visceral leishmaniasis