Glutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion

Naval P. Shanware, Kevin Bray, Christina H. Eng, Fang Wang, Maximillian Follettie, Jeremy Myers, Valeria R. Fantin and Robert T. Abraham ()
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Naval P. Shanware: Oncology Research Unit, Pfizer Worldwide Research and Development
Kevin Bray: Oncology Research Unit, Pfizer Worldwide Research and Development
Christina H. Eng: Oncology Research Unit, Pfizer Worldwide Research and Development
Fang Wang: Oncology Research Unit, Pfizer Worldwide Research and Development
Maximillian Follettie: Oncology Research Unit, Pfizer Worldwide Research and Development
Jeremy Myers: Oncology Research Unit, Pfizer Worldwide Research and Development
Valeria R. Fantin: Oncology Research Unit, Pfizer Worldwide Research and Development
Robert T. Abraham: Oncology Research Unit, Pfizer Worldwide Research and Development

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms5900

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