Bidirectional transport of amino acids regulates mTOR and autophagy.
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.
Nicklin
Paul
P
Respiratory Diseases Area, Novartis Institutes for BioMedical Research, Novartis Horsham Research Centre, West Sussex, UK.
Bergman
Philip
P
Zhang
Bailin
B
Triantafellow
Ellen
E
Wang
Henry
H
Nyfeler
Beat
B
Yang
Haidi
H
Hild
Marc
M
Kung
Charles
C
Wilson
Christopher
C
Myer
Vic E
VE
MacKeigan
Jeffrey P
JP
Porter
Jeffrey A
JA
Wang
Y Karen
YK
Cantley
Lewis C
LC
Finan
Peter M
PM
Murphy
Leon O
LO
D026962:Amino Acid Transport System ASC / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D004331:Drosophila melanogaster; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism
D026962:Amino Acid Transport System ASC; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D005973:Glutamine; D011494:Protein Kinases; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine