کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8323062 | 1539889 | 2014 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection
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کلمات کلیدی
MβCDbHLH-ZipSREBP cleavage activating proteinSCAPSREBP2OROUCP2DAPILDLRHMGCR6-diamidino-2-phenylindole - 6-دیامیدین-2-فنیلینولROS - ROSOil red O - روغن قرمز Oendoplasmic reticulum - شبکه آندوپلاسمی Plasma membrane - غشای پلاسماVisceral leishmaniasis - لیشمانیاز احشایی، کالاآزارMitochondria - میتوکندریاsterol regulatory element binding protein 2 - پروتئین اتصال دهنده عصاره استرول 2Uncoupling protein - پروتئین جدا کردنcholesterol - کلسترولReactive oxygen species - گونههای فعال اکسیژنlow density lipoprotein receptor - گیرنده لیپوپروتئین چگالی کم
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 55, October 2014, Pages 196-208
Journal: The International Journal of Biochemistry & Cell Biology - Volume 55, October 2014, Pages 196-208
نویسندگان
Madhuchhanda Mukherjee, Writoban Basu Ball, Pijush K. Das,