Editors' ChoiceCell Biology

mTORC1 goes sensorless

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Sci. Signal.  15 Jan 2019:
Vol. 12, Issue 564, eaaw6411
DOI: 10.1126/scisignal.aaw6411

A metabolite of leucine regulates mTORC1 through acetylation of Raptor in certain cell types and tissues.

The multiprotein complex mTORC1 stimulates anabolic processes, such as cell growth and proliferation, when nutrients are plentiful. In response to amino acids, such as leucine, mTORC1 translocates to lysosomes where it is activated. This translocation event requires the Rag complex. Several leucine sensors have been proposed for mTORC1, including Sestrin2, leucyl-tRNA synthetase, and glutamate dehydrogenase. Son et al. identified a mechanism by which leucine activates mTORC1 without a specific sensor. Leucine is metabolized to acetyl-CoA through a pathway that includes the enzyme 3-methylcrotonyl-CoA carboxylase (MCCC). Knockdown of MCCC in HeLa cells impaired the lysosomal translocation and activation of mTORC1, an effect that was rescued by the addition of DCA, a reagent that increases acetyl-CoA concentrations, but not by the addition of leucine. In amino acid–starved HeLa cells, SH-SY5Y neuroblastoma cells, primary neurons, and other cell types, the addition of leucine or DCA rescued mTORC1 activity. However, leucine and DCA did not have this effect in mouse embryonic fibroblasts (MEFs) or HEK293 cells. Individual knockdown of leucine sensors did not prevent DCA from rescuing mTORC1 activation in amino acid–starved HeLa cells. Lysine acetyltransferases add acetyl-CoA to target proteins, and the lysine acetyltransferase EP300 regulates mTORC1 signaling. Knockdown or pharmacological inhibition of EP300 prevented acetyl-CoA addition from rescuing mTORC1 inhibition in amino acid–starved HeLa cells. EP300 interacted with and acetylated Lys1097 in Raptor, and acetylation was reduced by amino acid starvation. A Raptor mutant that could not be acetylated at this site showed decreased interaction with the Rag complex, and cells expressing this mutant had reduced lysosomal recruitment of mTORC1. Raptor acetylation was decreased in the brains, livers, and skeletal muscle of fasted mice. Thus, acetyl-CoA derived from leucine promotes the activation of mTORC1 through acetylation of Raptor in certain cell types and tissues. The authors note that many of the previously published experiments delineating the mechanisms of mTORC1 activation by leucine have been performed largely in HEK293 cells and MEFs, cell types lacking the mechanism found by the authors.

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