Editors' ChoiceCell Biology

Doing the Glutamine Two-Step

Science Signaling  10 Feb 2009:
Vol. 2, Issue 57, pp. ec48
DOI: 10.1126/scisignal.257ec48

Activity of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which promotes protein translation and cell growth, depends on the availability of essential amino acids (EAA), such as leucine, and is also sensitive to the nonessential amino acid glutamine (see Cohen and Hall). Nicklin et al. found that the ability of EAA to stimulate rapamycin-sensitive phosphorylation of the mTORC1 target S6K1 (the 70-kD ribosomal protein S6 kinase) and that of its substrate ribosomal protein S6 in serum- and amino acid–starved HeLa cells depended on extracellular glutamine. Pretreatment with glutamine accelerated S6K1 phosphorylation in response to EAA compared to that seen in response to simultaneous administration of EAA and glutamine, whereas reversing the order of exposure, so that glutamine was administered after EAA, failed to stimulate S6K1 phosphorylation. Pharmacological analysis indicated that glutamine’s stimulation of mTORC1 signaling depended on its uptake by means of the SLC1A5 Na+-dependent glutamine transporter, and its subsequent exchange for EAA by means of the heterodimeric SLC7A5-SLC3A2 bidirectional transporter. Moreover, medium collected during exposure to EAA of cells preloaded with glutamine stimulated S6K1 phosphorylation in naïve starved cells; glutamine’s efflux in exchange for EAA was confirmed by analysis of glutamine in medium and of stable-isotope–labeled glutamine and leucine in medium and cell extracts. RNAi-mediated knockdown of SLC1A5, SLC7A5, or SLC3A2 inhibited mTORC1 signaling and led to a 10% decrease in cell size. Inhibition of mTORC1 signaling elicits autophagy; similarly, glutamine withdrawal or SLC1A5 knockdown promoted autophagy in RT112 cells. The authors thus conclude that the ability of EAA to enter cells and activate mTORC1 signaling depends on their exchange for glutamine. A similar dependence of mTORC1 signaling on extracellular glutamine was found in various other cell lines (including Drosophila S2 cells) but not in a line with high basal concentrations of glutamine, leading to the intriguing suggestion that some tumor cells could be “primed” by high endogenous glutamine for mTORC1 signaling.

P. Nicklin, P. Bergman, B. Zhang, E. Triantafellow, H. Wang, B. Nyfeler, H. Yang, M. Hild, C. Kung, C. Wilson, V. E. Myer, J. P. MacKeigan, J.A. Porter, Y. K. Wang, L. C. Cantley, P. M. Finan, L. O. Murphy, Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009). [Online Journal]

A. Cohen, M. N. Hall, An amino acid shuffle activates mTORC1. Cell 136, 399–400 (2009). [Online Journal]