Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1.

Cell Rep
Authors
Keywords
Abstract

mTORC1 controls key processes that regulate cell growth, including mRNA translation, ribosome biogenesis, and autophagy. Environmental amino acids activate mTORC1 by promoting its recruitment to the cytosolic surface of the lysosome, where its kinase is activated downstream of growth factor signaling. mTORC1 is brought to the lysosome by the Rag GTPases, which are tethered to the lysosomal membrane by Ragulator, a lysosome-bound scaffold. Here, we identify c17orf59 as a Ragulator-interacting protein that regulates mTORC1 activity through its interaction with Ragulator at the lysosome. The binding of c17orf59 to Ragulator prevents Ragulator interaction with the Rag GTPases, both in cells and in vitro, and decreases Rag GTPase lysosomal localization. Disruption of the Rag-Ragulator interaction by c17orf59 impairs mTORC1 activation by amino acids by preventing mTOR from reaching the lysosome. By disrupting the Rag-Ragulator interaction to inhibit mTORC1, c17orf59 expression may represent another mechanism to modulate nutrient sensing by mTORC1.

Year of Publication
2015
Journal
Cell Rep
Volume
12
Issue
9
Pages
1445-55
Date Published
2015 Sep 01
ISSN
2211-1247
URL
DOI
10.1016/j.celrep.2015.07.052
PubMed ID
26299971
PubMed Central ID
PMC4570232
Links
Grant list
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
R21 AG042876 / AG / NIA NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 CA129105 / CA / NCI NIH HHS / United States
R21 AG042876-01A1 / AG / NIA NIH HHS / United States