Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex

Castellano, Brian M.; Thelen, Ashley M.; Moldavski, Ofer; Feltes, McKenna; Welle, Reini E.N. van der; Mydock-McGrane, Laurel; Jiang, Xuntian; Eijkeren, Robert J van; Davis, Oliver B.; Louie, Sharon M.; Perera, Rushika M.; Covey, Douglas F.; Nomura, Daniel K.; Ory, Daniel S.; Zoncu, Roberto

doi:10.1126/science.aag1417

Cited by 435 publications

(468 citation statements)

References 36 publications

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“…In our previous work, we found that SLC38A9 and the cytosolic sensor CASTOR1 both contribute to arginine sensing by mTORC1 (Chantranupong et al, 2016; Wang et al, 2015), and we hypothesize that different cell types use these sensing branches to varying extents, depending on whether they obtain amino acids mostly in the free form or through the digestion of proteins. Recent work shows that SLC38A9 also has an important role in cholesterol sensing upstream of mTORC1 (Castellano et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Wyant

Abu-Remaileh

Wolfson

et al. 2017

Cell

379

352

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Summary The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.

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Section: Discussionmentioning

confidence: 99%

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Wyant

Abu-Remaileh

Wolfson

et al. 2017

Cell

379

352

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“…In particular, cholesterol delivered to the lysosome by endocytosed LDL particles induced the recruitment of mTORC1 to the lysosomal surface (Castellano et al, 2017). Combining in vitro and in cell experiments, it was shown that lysosomal cholesterol levels affect the activation status of the Rag GTPases.…”

Section: Feedback Regulation Of Mtorc1 Activity By Lipid-derived Signalsmentioning

confidence: 99%

Emerging Roles for the Lysosome in Lipid Metabolism

Thelen

Zoncu

2017

Trends in Cell Biology

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207

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Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and non-vesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease.

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“…In mammalian cells, amino acids, along with glucose and cholesterol, trigger the lysosomal translocation of mTORC1 via a mechanism that requires the Ras-related, heterodimeric Rag guanosine triphosphatases (GTPases) and the pentameric Ragulator complex Castellano et al, 2017;Efeyan et al, 2013;Sancak et al, 2008Sancak et al, , 2010. The Rag GTPases, composed of RagA or RagB (which are functionally equivalent to each other) in complex with RagC or RagD (also functionally equivalent), are thought to directly bind to the Raptor subunit of mTORC1, anchoring it to the lysosomal membrane (Kim et al, 2008;Sancak et al, 2008Sancak et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%