Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9

J Jung, HM Genau, C Behrends - Molecular and cellular biology, 2015 - Taylor & Francis
J Jung, HM Genau, C Behrends
Molecular and cellular biology, 2015Taylor & Francis
The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many
cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on
lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling
protein translation and cell growth. Here, we identify the human 11-pass transmembrane
protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes
with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases …
The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner. Depletion of SLC38A9 inhibits mTORC1 activity in the presence of amino acids and in response to amino acid replenishment following starvation. Conversely, SLC38A9 overexpression causes RHEB (Ras homolog enriched in brain) GTPase-dependent hyperactivation of mTORC1 and partly sustains mTORC1 activity upon amino acid deprivation. Intriguingly, during amino acid starvation mTOR is retained at the lysosome upon SLC38A9 depletion but fails to be activated. Together, the findings of our study reveal SLC38A9 as a Rag-Ragulator complex member transducing amino acid availability to mTORC1 activity.
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