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SREBP-1a–stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1

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Author(s)
Jae-Ho LeePeter PhelanMinsang ShindByung-Chul OhXianlin HanSeung-Soon ImTimothy F. Osborne
Keimyung Author(s)
Lee, Jae HoIm, Seung Soon
Department
Dept. of Anatomy (해부학)
Dept. of Physiology (생리학)
Journal Title
Proceedings of the National Academy of Science of USA(PNAS)
Issued Date
2018
Volume
115
Issue
52
Keyword
macrophageslipid synthesismTORC1TLR4SREBPs
Abstract
There is a growing appreciation for a fundamental connection between lipid metabolism and the immune response. Macrophage phagocytosis is a signature innate immune response to pathogen exposure, and cytoplasmic membrane expansion is required to engulf the phagocytic target. The sterol regulatory element binding proteins (SREBPs) are key transcriptional regulatory proteins that sense the intracellular lipid environment and modulate expression of key genes of fatty acid and cholesterol metabolism to maintain lipid homeostasis. In this study, we show that TLR4-dependent stimulation of macrophage phagocytosis requires mTORC1-directed SREBP-1a−dependent lipid synthesis. We also show that the phagocytic defect in macrophages from SREBP-1a−deficient mice results from decreased interaction between membrane lipid rafts and the actin cytoskeleton, presumably due to reduced accumulation of newly synthesized fatty acyl chains within major membrane phospholipids. We show that mTORC1-deficient macrophages also have a phagocytic block downstream from TLR4 signaling, and, interestingly, the reduced level of phagocytosis in both SREBP-1a− and mTORC1-deficient macrophages can be restored by ectopic SREBP-1a expression. Taken together, these observations indicate SREBP-1a is a major downstream effector of TLR4−mTORC1 directed interactions between membrane lipid rafts and the actin cytoskeleton that are required for pathogen-stimulated phagocytosis in macrophages.
Keimyung Author(s)(Kor)
이재호
임승순
Publisher
School of Medicine (의과대학)
Citation
Jae-Ho Lee et al. (2018). SREBP-1a–stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1. Proceedings of the National Academy of Science of USA(PNAS), 115(52), E12228–E12234. doi: 10.1073/pnas.1813458115
Type
Article
ISSN
1091-6490
Source
https://www.pnas.org/content/115/52/E12228.long
DOI
10.1073/pnas.1813458115
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41837
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Anatomy (해부학)
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
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