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Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

ABSTRACT: Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drives macrophage activation, prolonged exposure to LPS triggers tolerance to LPS, where macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response is modulated by GPD2, which coordinates a shutdown of oxidative metabolism; this limits the availability of acetyl coenzyme A for histone acetylation at genes encoding inflammatory mediators and thus contributes to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.

SUBMITTER: Langston PK

PROVIDER: S-EPMC6707851 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

Langston P Kent PK Nambu Aya A Jung Jonathan J Shibata Munehiko M Aksoylar H Ibrahim HI Lei Jiahui J Xu Peining P Doan Mary T MT Jiang Helen H MacArthur Michael R MR Gao Xia X Kong Yong Y Chouchani Edward T ET Locasale Jason W JW Snyder Nathaniel W NW Horng Tiffany T

Nature immunology 20190805 9

Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory m ...[more]

PMID: 31384058

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Project description:The glycerol-3-phosphate (G-3-P) shuttle is an important pathway for delivery of cytosolic reducing equivalents into mitochondrial oxidative phosphorylation, and plays essential physiological roles in yeast, plants, and animals. However, its role has been unclear in filamentous and pathogenic fungi. Here, we characterize the function of the G-3-P shuttle in Pyricularia oryzae by genetic and molecular analyses. In P. oryzae, a glycerol-3-phosphate dehydrogenase 1 (PoGpd1) is involved in NO production, conidiation, and utilization of several carbon sources (pyruvate, sodium acetate, glutamate, and glutamine). A glycerol-3-phosphate dehydrogenase 2 (PoGpd2) is essential for glycerol utilization and fungal development. Deletion of PoGPD2 led to delayed aerial hyphal formation, accelerated aerial hyphal collapse, and reduced conidiation on complete medium (CM) under a light-dark cycle. Aerial mycelial surface hydrophobicity to water and Tween 20 was decreased in ?Pogpd2. Melanin synthesis genes required for cell wall construction and two transcription factor genes (COS1 and CONx2) required for conidiation and/or aerial hyphal differentiation were down-regulated in the aerial mycelia of ?Pogpd2 and ?Pogpd1. Culturing under continuous dark could complement the defects of aerial hyphal differentiation of ?Pogpd2 observed in a light-dark cycle. Two light-sensitive protein genes (PoSIR2 encoding an NAD+-dependent deacetylase and TRX2 encoding a thioredoxin 2) were up-regulated in ?Pogpd2 cultured on CM medium in a light-dark cycle. ?Pogpd2 showed an increased intracellular NAD+/NADH ratio and total NAD content, and alteration of intracellular ATP production. Culturing on minimal medium also could restore aerial hyphal differentiation of ?Pogpd2, which is deficient on CM medium in a light-dark cycle. Two glutamate synthesis genes, GDH1 and PoGLT1, which synthesize glutamate coupled with oxidation of NADH to NAD+, were significantly up-regulated in ?Pogpd2 in a light-dark cycle. Moreover, deletion of PoGpd1 or PoGpd2 led to reduced virulence of conidia or hyphae on rice. The glycerol-3-phosphate shuttle is involved in cellular redox, fungal development, and virulence in P. oryzae.

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Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

Publications

Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

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