Sci. Signal., 9 October 2012
Cell Biology Tasting Amino Acids Limits Autophagy
Science Signaling, AAAS, Washington, DC 20005, USA
Amino acids stimulate the activity of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which activates p70 ribosomal protein S6 kinase (S6K) and 4E binding protein 1 (4EBP-1) to promote translation initiation and inhibits the kinase ULK1 to suppress autophagy. Amino acids also trigger the translocation of mTORC1 to lysosomes. The G protein–coupled taste receptor complex T1R1 and T1R3 (T1R1/T1R3) is activated by amino acids, and Wauson et al. identified this complex as an amino acid sensor for mTORC1. In MIN6 pancreatic β cells and H9C2 cardiac myoblasts, knockdown of either T1R3 or T1R1 reduced activation of mTORC1 by amino acids (as assessed by phosphorylation of S6K), and in various cell lines, pharmacological inhibition of T1R3 reduced phosphorylation of S6K in response to amino acid stimulation. Furthermore, amino acid–triggered translocation of mTORC1 to lysosomes in HeLa cells was reduced by knockdown of T1R3. Activated 4EBP-1 recruits the small ribosomal subunit eIF4G to capped mRNAs, an event required to initiate translation, and knockdown of T1R3 in MIN6 cells or H9C2 cells reduced basal and amino acid–induced phosphorylation and activation of 4EBP-1 as well as recruitment of eIF4G to the mRNA cap and decreased basal and amino acid–induced insulin secretion from MIN6 cells due to reduced translation of the mRNA encoding preproinsulin. T1R3–/– mice showed reduced activation of mTOR in skeletal muscle and heart compared to wild-type mice. Amino acid stimulation of MIN6 activated extracellular signal–regulated kinase (ERK) 1/2 in a T1R1- and T1R3-dependent manner. Activation of T1R1/T1R3 also stimulates the activity of phospholipase Cβ and triggers calcium influx, and pharmacological inhibition of ERK1/2, phospholipase Cβ, or calcium influx through L-type calcium channels reduced amino acid–induced activation of mTORC1 in MIN6 cells. Autophagy increases in response to amino acid deprivation, and knockdown of T1R3 in H9C2 or HeLa cells increased basal and starvation-induced autophagy and reduced phosphorylation (and inhibition) of ULK1. Furthermore, T1R3–/– mice showed higher rates of autophagy as assessed by decreased accumulation of p62 (which directs polyubiquitinated or aggregated proteins to the autophagosome) in various tissues in response to fasting. Thus, the taste receptor complex T1R1/T1R3 is an amino acid sensor for mTORC1.
E. M. Wauson, E. Zaganjor, A-Y. Lee, M. L. Guerra, A. B. Ghosh, A. L. Bookout, C. P. Chambers, A. Jivan, K. McGlynn, M. R. Hutchison, R. J. Deberardinis, M. H. Cobb, The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy. Mol. Cell 47, 851–862 (2012). [PubMed]
Citation: W. Wong, Tasting Amino Acids Limits Autophagy. Sci. Signal. 5, ec261 (2012).
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