Glutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion

The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, inter...

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Veröffentlicht in:Nature communications 2014-09, Vol.5 (1), p.4900-4900, Article 4900
Hauptverfasser: Shanware, Naval P., Bray, Kevin, Eng, Christina H., Wang, Fang, Follettie, Maximillian, Myers, Jeremy, Fantin, Valeria R., Abraham, Robert T.
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Sprache:eng
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Zusammenfassung:The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, interleukin-8 (IL-8). Glutamine deprivation-induced ER stress triggers colocalization of autophagosomes, lysosomes and the Golgi into a subcellular structure whose integrity is essential for IL-8 secretion. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates. The protein kinase, mTOR, is also colocalized with the lysosomal membrane clusters induced by glutamine deprivation, and inhibition of mTORC1 activity abolishes both endomembrane reorganization and IL-8 secretion. Activated mTORC1 elicits IL8 gene expression via the activation of an IRE1-JNK signalling cascade. Treatment of cells with a glutaminase inhibitor phenocopies glutamine restriction, suggesting that these results will be relevant to the clinical development of glutamine metabolism inhibitors as anticancer agents. Glutamine deprivation is currently being tested as a therapeutic strategy in cancer. Shanware et al. show that in cultured cells, glutamine deprivation stimulates IL-8 secretion by triggering endoplasmic reticulum stress, and suggest that the potential of this effect to influence tumour development should be examined.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms5900