A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect

López-Serra, Paula; Marcilla, Miguel; Villanueva, Alberto; Ramos-Fernández, António; Palau, Anna M.; Leal, Lucía; Wahi, Jessica E.; Setien-Baranda, Fernando; Szczesna, Karolina; Moutinho, Cátia; Martínez-Cardús, Anna; Heyn, Holger; Sandoval, Juan; Puertas, Sara; Vidal, August; Sanjuán, Xavier; Martínez-Balibrea, Eva; Viñals, Francesc; Perales, José C.; Bramsem, Jesper B.; Ørntoft, Torben F.; Andersen, Claus Lindbjerg; Tabernero, Josep; McDermott, Ultan; Boxer, Matthew B.; Heiden, Matthew G. Vander; Albar, Juan Pablo; Esteller, Manel

doi:10.1038/ncomms4608

Cited by 96 publications

(73 citation statements)

References 50 publications

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“…The question then arises as to how the protein expression of GLUT1 is upregulated in aged lung. The answer could be provided by previous publications that show that GLUT1 expression, at least in part, is regulated by a protein degradation pathway (35,36). Alterations in protein turnover during biological aging have been correlated with decreased activity of the proteasome system and autophagy (37), which may account for the increase in GLUT1 expression in the aged lung.…”

Section: Discussionmentioning

confidence: 99%

Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

Cho

Moon

Lee

et al. 2017

Am J Respir Cell Mol Biol

107

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Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)-induced glycolysis regulates age-dependent fibrogenesis of the lung. Mouse and human lung tissues were analyzed for GLUT1 and glycolytic markers using immunoblotting. Glycolytic function was measured using a Seahorse apparatus. To study the effect of GLUT1, genetic inhibition of GLUT1 was performed by short hairpin RNA transduction, and phloretin was used for pharmacologic inhibition of GLUT1. GLUT1-dependent glycolysis is activated in aged lung. Genetic and pharmacologic inhibition of GLUT1 suppressed the protein expression of a-smooth muscle actin, a key cytoskeletal component of activated fibroblasts, in mouse primary lung fibroblast cells. Moreover, we demonstrated that the activation of AMPactivated protein kinase, which is regulated by GLUT1-dependent glycolysis, represents a critical metabolic pathway for fibroblast activation. Furthermore, we demonstrated that phloretin, a potent inhibitor of GLUT1, significantly inhibited bleomycin-induced lung fibrosis in vivo. These results suggest that GLUT1-dependent glycolysis regulates fibrogenesis in aged lung and that inhibition of GLUT1 provides a potential target of therapy of age-related lung fibrosis.

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Section: Discussionmentioning

confidence: 99%

Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

Cho

Moon

Lee

et al. 2017

Am J Respir Cell Mol Biol

107

View full text Add to dashboard Cite

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“…Crucially, cells unresponsive to HER2-targeting drugs are sensitive to ERAD inhibition, displaying the ERAD 'addiction' alluded to above. However, the opposite of this has been observed for Derlin3, whose expression is silenced in some colorectal cancer lines [73]. In fact, Derlin3 promotes ERAD of the glucose transporter Glut1.…”

Section: Physiolgoical and Pathological Roles Of Mammalian Derlinsmentioning

confidence: 96%

“…In fact, Derlin3 promotes ERAD of the glucose transporter Glut1. Tumor-associated epigenetic silencing of Derlin3 hence elevates Glut1 levels, allowing a shift in tumor cell metabolism, from oxidative phosphorylation to glycolysis -a characteristic of cancer [73].…”

Section: Physiolgoical and Pathological Roles Of Mammalian Derlinsmentioning

confidence: 99%

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Lemberg

Adrain

2016

Seminars in Cell & Developmental Biology

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Rhomboids, proteases containing an unusual membrane-integral serine protease active site, were first identified in Drosophila, where they fulfill an essential role in epidermal growth factor receptor signaling, by cleaving membrane-tethered growth factor precursors. It has recently become apparent that eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms. Here we highlight how loss of proteolytic activity was followed in evolution by impressive functional diversification, enabling these pseudoproteases to fulfill crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling. We distil the current understanding of the roles of rhomboid pseudoproteases in development and disease.

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“…The approximately 4% of signals with the lowest quality were removed prior to further analysis. Differential regulation was measured using linear models (López-Serra et al, 2014), and statistical significance was measured using q values (FDR). All analyses were conducted using software from Proteobotics.…”

Section: Proteomics Data Analysismentioning

confidence: 99%

Arabidopsis Responds to Alternaria alternata Volatiles by Triggering Plastid Phosphoglucose Isomerase-Independent Mechanisms

et al. 2016

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Volatile compounds (VCs) emitted by phylogenetically diverse microorganisms (including plant pathogens and microbes that do not normally interact mutualistically with plants) promote photosynthesis, growth, and the accumulation of high levels of starch in leaves through cytokinin (CK)-regulated processes. In Arabidopsis (Arabidopsis thaliana) plants not exposed to VCs, plastidic phosphoglucose isomerase (pPGI) acts as an important determinant of photosynthesis and growth, likely as a consequence of its involvement in the synthesis of plastidic CKs in roots. Moreover, this enzyme plays an important role in connecting the CalvinBenson cycle with the starch biosynthetic pathway in leaves. To elucidate the mechanisms involved in the responses of plants to microbial VCs and to investigate the extent of pPGI involvement, we characterized pPGI-null pgi1-2 Arabidopsis plants cultured in the presence or absence of VCs emitted by Alternaria alternata. We found that volatile emissions from this fungal phytopathogen promote growth, photosynthesis, and the accumulation of plastidic CKs in pgi1-2 leaves. Notably, the mesophyll cells of pgi1-2 leaves accumulated exceptionally high levels of starch following VC exposure. Proteomic analyses revealed that VCs promote global changes in the expression of proteins involved in photosynthesis, starch metabolism, and growth that can account for the observed responses in pgi1-2 plants. The overall data show that Arabidopsis plants can respond to VCs emitted by phytopathogenic microorganisms by triggering pPGI-independent mechanisms.

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A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect

Cited by 96 publications

References 50 publications

Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Arabidopsis Responds to Alternaria alternata Volatiles by Triggering Plastid Phosphoglucose Isomerase-Independent Mechanisms

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