GLUT6 is a lysosomal transporter that is regulated by inflammatory stimuli and modulates glycolysis in macrophages

Maedera, Shotaro; Mizuno, Tadahaya; Ishiguro, Hiromu; Ito, Takuya; Soga, Tomoyoshi; Kusuhara, Hiroyuki

doi:10.1002/1873-3468.13298

Cited by 57 publications

(45 citation statements)

References 39 publications

(52 reference statements)

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“…Of note, CG4607 and CG1208 belong to the SLC2 family of hexose sugar transporters and are orthologous to SLC2A6/GLUT6 or SLC2A8/GLUT8 in humans. Importantly, it has recently been demonstrated that GLUT6 acts as a lysosomal transporter, which is regulated by inflammatory stimuli (Maedera et al, 2019) and is strongly upregulated in macrophages activated by LPS (Caruana et al, 2019). Similarly, in Drosophila, immune activation is energy demanding and glucose may be used as a major source of energy for the production of mature LMs (Bajgar et al, 2015).…”

Section: Lamellocyte Sub-clustering Identifies Lm Intermediates and Smentioning

confidence: 99%

A single-cell survey ofDrosophilablood

Tattikota

Liu

et al. 2019

Preprint

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SummaryDrosophila blood cells, called hemocytes, are classified into plasmatocytes, crystal cells, and lamellocytes based on the expression of a few marker genes and cell morphologies, which are inadequate to classify the complete hemocyte repertoire. Here, we used single-cell RNA sequencing (scRNA-seq) to map hemocytes across different inflammatory conditions in larvae. We resolved plasmatocytes into different states based on the expression of genes involved in cell cycle, antimicrobial response, and metabolism together with the identification of intermediate states. Further, we discovered rare subsets within crystal cells and lamellocytes that express fibroblast growth factor (FGF) ligand branchless and receptor breathless, respectively. We demonstrate that these FGF components are required for mediating effective immune responses against parasitoid wasp eggs, highlighting a novel role for FGF signaling in inter-hemocyte crosstalk. Our scRNA-seq analysis reveals the diversity of hemocytes and provides a rich resource of gene expression profiles for a systems-level understanding of their functions.HighlightsscRNA-seq of Drosophila blood recovers plasmatocytes, crystal cells, and lamellocytesscRNA-seq identifies different plasmatocyte states based on the expression of genes involved in cell cycle regulation, antimicrobial response, and metabolismPseudotemporal ordering of single cells identifies crystal cell and lamellocyte intermediate statesscRNA-seq uncovers a novel role for FGF signaling in inter-hemocyte crosstalk

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Section: Lamellocyte Sub-clustering Identifies Lm Intermediates and Smentioning

confidence: 99%

A single-cell survey ofDrosophilablood

Tattikota

Liu

et al. 2019

Preprint

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“…In mice, Glut6 is upregulated by activation of T lymphocytes [51], while in humans, the GLUT6 protein concentration was shown to increase in CD4+ T cells on HIV-1 infection [52]. Recently, GLUT6 was shown to be a lysosomal transporter regulated by inflammatory stimuli and modulating glycolysis in macrophages [53] Glut6 knock-out mice had decreased resistance to LPS-induced shock [53].…”

Section: Discussionmentioning

confidence: 99%

Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

Franaszczyk

Truszkowska

Chmielewski

et al. 2020

JCM

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The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.

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“…Interestingly CD8 + EMRAs displayed increased expression of the glucose transporters glut8 and -10. It is tempting to speculate in the light of a recent publication showing that glut6 functions as a glycolysis modulator in inflammatory macrophages without influencing glucose uptake 49 , that glut8 and -10 may act in a similar manner in senescent CD8 + T cells. Glut6, -8 and -10 are all members of the Glut III family of transporters, with glut6 and -8 being very closely located on chromosome 9 and glut10 having a very high affinity for both 2-deoxy-D-glucose and D-galactose 50 , both slow the rate of glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial mass governs the extent of T cell senescence

Callender

Carroll

Bober

et al. 2019

Preprint

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The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than the CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8+ T cells has knock‐on consequences for nutrient usage, metabolism and function. Senescent CD4+ T cells uptake more lipid and glucose than their CD8+ counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4+ T cells allows for more proliferation and migration than observed in the senescent CD8+ subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4+ T cells, through the addition of low‐dose rotenone, causes the generation of a CD4+ T cell with a CD8+‐like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.

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GLUT6 is a lysosomal transporter that is regulated by inflammatory stimuli and modulates glycolysis in macrophages

Cited by 57 publications

References 39 publications

A single-cell survey ofDrosophilablood

A single-cell survey ofDrosophilablood

Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

Mitochondrial mass governs the extent of T cell senescence

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