气候变化领域集成服务门户(CCPortal): SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress

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DOI	10.1073/pnas.2100295118
	SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress
	Kobayashi T.; Nguyen-Tien D.; Sorimachi Y.; Sugiura Y.; Suzuki T.; Karyu H.; Shimabukuro-Demoto S.; Uemura T.; Okamura T.; Taguchi T.; Ueki K.; Kato N.; Goda N.; Dohmae N.; Takubo K.; Suematsu M.; Toyama-Sorimachi N.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR) 7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient bio-transformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Amino acid transporter; Cytokine; Immunometabolism; Innate immune cell; Macrophage
语种	英语
scopus关键词	amino acid; amino acid transporter; cytokine; diaminopimelic acid; excitatory amino acid transporter 4; glucose; hydroxymethylglutaryl coenzyme A reductase kinase; oligopeptide; peptide transporter 1; pyruvic acid; rapamycin; toll like receptor; animal cell; Article; controlled study; cytokine production; flow cytometry; glucose transport; glycolysis; human; human cell; immunoblotting; immunocompetent cell; immunohistochemistry; immunoprecipitation; inflammation; liquid chromatography; lysosome; M1 macrophage; mass spectrometry; metabolic regulation; metabolic stress; mouse; nonhuman; oligomerization; pathogenesis
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238826
作者单位	Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan; Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan; Department of Biochemistry, Keio University, School of Medicine, Tokyo, 160-8582, Japan; Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan; Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan; Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Miyagi, 980-8578, Japan; Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan; ...
推荐引用方式 GB/T 7714	Kobayashi T.,Nguyen-Tien D.,Sorimachi Y.,et al. SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress[J],2021,118(33).
APA	Kobayashi T..,Nguyen-Tien D..,Sorimachi Y..,Sugiura Y..,Suzuki T..,...&Toyama-Sorimachi N..(2021).SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Kobayashi T.,et al."SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).