Folliculin promotes substrate-selective mTORC1 activity by activating RagC to recruit TFE3.
Folliculin promotes substrate-selective mTORC1 activity by activating RagC to recruit TFE3.
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DOI：
10.1371/journal.pbio.3001594
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发表时间：
2022-03
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
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Mechanistic target of rapamycin complex I (mTORC1) is central to cellular metabolic regulation. mTORC1 phosphorylates a myriad of substrates, but how different substrate specificity is conferred on mTORC1 by different conditions remains poorly defined. Here, we show how loss of the mTORC1 regulator folliculin (FLCN) renders mTORC1 specifically incompetent to phosphorylate TFE3, a master regulator of lysosome biogenesis, without affecting phosphorylation of other canonical mTORC1 substrates, such as S6 kinase. FLCN is a GTPase-activating protein (GAP) for RagC, a component of the mTORC1 amino acid (AA) sensing pathway, and we show that active RagC is necessary and sufficient to recruit TFE3 onto the lysosomal surface, allowing subsequent phosphorylation of TFE3 by mTORC1. Active mutants of RagC, but not of RagA, rescue both phosphorylation and lysosomal recruitment of TFE3 in the absence of FLCN. These data thus advance the paradigm that mTORC1 substrate specificity is in part conferred by direct recruitment of substrates to the subcellular compartments where mTORC1 resides and identify potential targets for specific modulation of specific branches of the mTOR pathway. How does the mTORC1 complex, which influences myriad cellular processes, achieve specificity? This study shows that substrate specificity is in part conferred by modulating the recruitment of substrates, in this case the transcription factor TFE3, to mTORC1.
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影响因子：
56.9
作者：
Lawrence, Rosalie E.;Fromm, Simon A.;Zoncu, Roberto
通讯作者：
Zoncu, Roberto
影响因子：
7.3
作者：
Martina JA;Diab HI;Lishu L;Jeong-A L;Patange S;Raben N;Puertollano R
通讯作者：
Puertollano R
影响因子：
5.6
作者：
Salma N;Song JS;Arany Z;Fisher DE
通讯作者：
Fisher DE
影响因子：
16
作者：
Tsun ZY;Bar-Peled L;Chantranupong L;Zoncu R;Wang T;Kim C;Spooner E;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1126/science.aag2553
发表时间：
2017-06-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Di Malta C;Siciliano D;Calcagni A;Monfregola J;Punzi S;Pastore N;Eastes AN;Davis O;De Cegli R;Zampelli A;Di Giovannantonio LG;Nusco E;Platt N;Guida A;Ogmundsdottir MH;Lanfrancone L;Perera RM;Zoncu R;Pelicci PG;Settembre C;Ballabio A
通讯作者：
Ballabio A