Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids

Abstract

The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…Amino acid levels are linked to mTOR through a mechanism that is dependent, at least to some extent, on p62/ SQSTM1 (Duran et al 2011): mTORC1 associates with the amino acid sensing Rag family of small GTPases (Kim et al 2008;Sancak et al 2008) on the surface of lysosomes (Sancak et al 2010). p62/SQSTM1 mediates this process by associating with Raptor, a subunit of the mTORC1 complex, and the Rag GTPases, thereby forming a high molecular weight complex that relays the signal from amino acids to the mTORC1 pathway (Duran et al 2011).…”

dRAGging Amino Acid-mTORC1 Signaling by SH3BP4

“…Rag GTPases interact with a lysosomal multiprotein complex termed Ragulator that consists of MP1, p14, p18, HBXIP and C7orf59 (Bar-Peled et al, 2012;Sancak et al, 2010). Ragulator is necessary for the localization of Rag GTPases to the lysosomal surface.…”

“…Ragulator is necessary for the localization of Rag GTPases to the lysosomal surface. Through interaction with Ragulator, Rag GTPases can be present on the lysosomal membrane regardless of their nucleotide bound state or the availability of amino acids (Sancak et al, 2010). The interaction between Ragulator and Rag GTPases is important for activation of mTORC1 since Rag GTPases need to recruit mTORC1 to the lysosome for the activation of mTORC1 by Rheb.…”

“…RagA and RagB recruit mTORC1 via binding to raptor under amino acid-enriched conditions (Binda et al, 2009;Sancak et al, 2010). Once mTORC1 is recruited to the lysosome, it is activated by Rheb that resides on the lysosomal membrane (Sancak et al, 2010).…”

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

“…Similarly, hypoxia induces the expression of REDD1 (for regulated in development and DNA damage responses), which stimulates TSC activity and, in turn, suppression of mTORC1. Finally, the presence of amino acids allows the activation of mTOR by Rheb, in part through the Rag GTPase-mediated translocation of mTOR to the lysosomal surface (Sancak et al, 2010). Amino-acid starvation, which inhibits mTOR, also facilitates autophagosome-lysosome fusion through lysosome clustering (Korolchuk et al, 2011).…”