RapamycinFungusV1, Main, Exploration, bibRecord, 000499

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

Identifieur interne : 000499 ( Main/Exploration ); précédent : 000498; suivant : 000500

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

Auteurs : Jae-Ho Lee [Corée du Sud] ; Peter Phelan [États-Unis] ; Minsang Shin [Corée du Sud] ; Byung-Chul Oh [Corée du Sud] ; Xianlin Han [États-Unis] ; Seung-Soon Im [Corée du Sud] ; Timothy F. Osborne [Corée du Sud, États-Unis]

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2018.

RBID : pubmed:30530672

Descripteurs français

English descriptors

KwdEn :
- Animals (MeSH), Cells, Cultured (MeSH), Lipids (biosynthesis), Macrophages (metabolism), Mechanistic Target of Rapamycin Complex 1 (genetics), Mechanistic Target of Rapamycin Complex 1 (metabolism), Mice (MeSH), Mice, Inbred C57BL (MeSH), Mice, Knockout (MeSH), Phagocytosis (MeSH), Sterol Regulatory Element Binding Protein 1 (genetics), Sterol Regulatory Element Binding Protein 1 (metabolism), Toll-Like Receptor 4 (genetics), Toll-Like Receptor 4 (metabolism).
MESH :
- chemical , biosynthesis : Lipids.
- chemical , genetics : Mechanistic Target of Rapamycin Complex 1, Sterol Regulatory Element Binding Protein 1, Toll-Like Receptor 4.
- metabolism : Macrophages, Mechanistic Target of Rapamycin Complex 1, Sterol Regulatory Element Binding Protein 1, Toll-Like Receptor 4.
- Animals, Cells, Cultured, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis.

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.

DOI: 10.1073/pnas.1813458115
PubMed: 30530672
PubMed Central: PMC6310840

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000393
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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Cells, Cultured (MeSH)</term>
<term>Lipids (biosynthesis)</term>
<term>Macrophages (metabolism)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (genetics)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
<term>Mice, Knockout (MeSH)</term>
<term>Phagocytosis (MeSH)</term>
<term>Sterol Regulatory Element Binding Protein 1 (genetics)</term>
<term>Sterol Regulatory Element Binding Protein 1 (metabolism)</term>
<term>Toll-Like Receptor 4 (genetics)</term>
<term>Toll-Like Receptor 4 (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Cellules cultivées (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (génétique)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Lipides (biosynthèse)</term>
<term>Macrophages (métabolisme)</term>
<term>Phagocytose (MeSH)</term>
<term>Protéine-1 de liaison à l'élément de régulation des stérols (génétique)</term>
<term>Protéine-1 de liaison à l'élément de régulation des stérols (métabolisme)</term>
<term>Récepteur de type Toll-4 (génétique)</term>
<term>Récepteur de type Toll-4 (métabolisme)</term>
<term>Souris (MeSH)</term>
<term>Souris de lignée C57BL (MeSH)</term>
<term>Souris knockout (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Lipids</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Sterol Regulatory Element Binding Protein 1</term>
<term>Toll-Like Receptor 4</term>
</keywords>
<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Lipides</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Protéine-1 de liaison à l'élément de régulation des stérols</term>
<term>Récepteur de type Toll-4</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Macrophages</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Sterol Regulatory Element Binding Protein 1</term>
<term>Toll-Like Receptor 4</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Macrophages</term>
<term>Protéine-1 de liaison à l'élément de régulation des stérols</term>
<term>Récepteur de type Toll-4</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cells, Cultured</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
<term>Phagocytosis</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules cultivées</term>
<term>Phagocytose</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
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<DateCompleted><Year>2019</Year>
<Month>03</Month>
<Day>22</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>09</Day>
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<Issue>52</Issue>
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<Month>12</Month>
<Day>26</Day>
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<Title>Proceedings of the National Academy of Sciences of the United States of America</Title>
<ISOAbbreviation>Proc Natl Acad Sci U S A</ISOAbbreviation>
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<ArticleTitle>SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1.</ArticleTitle>
<Pagination><MedlinePgn>E12228-E12234</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1813458115</ELocationID>
<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>Copyright © 2018 the Author(s). Published by PNAS.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Jae-Ho</ForeName>
<Initials>JH</Initials>
<AffiliationInfo><Affiliation>Department of Physiology, Keimyung University School of Medicine, 42601 Daegu, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Phelan</LastName>
<ForeName>Peter</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Institute for Fundamental Biomedical Research, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medicine, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shin</LastName>
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	Serveur d'exploration sur la rapamycine et les champignons
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Serveur d'exploration sur la rapamycine et les champignons

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

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

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