Abstract
Amino acids stimulate the eukaryotic target of rapamycin complex 1 (TORC1), and hence growth, through the Rag GTPases and their regulators. Among these, the yeast Lst4-Lst7 Rag GTPase GAP complex clusters, as we previously reported, at the vacuolar membrane upon amino acid starvation. In response to amino acid refeeding, it activates the Rag GTPase-TORC1 branch and is then dispersed from the vacuolar surface. Here, we show that the latter effect is driven by TORC1 itself, which directly phosphorylates several residues within the intra-DENN loop of Lst4 that, only in its non-phosphorylated state, tethers the Lst4-Lst7 complex to the vacuolar membrane. An Lst4 variant disrupting this feedback inhibition mechanism causes TORC1 hyperactivation and proliferation defects in cells grown on poor nitrogen sources. Thus, we identify Lst4 asaTORC1 target and key node of a homeostatic mechanism that adjusts TORC1 activity to the availability of amino acids.
Highlights
The eukaryotic target of rapamycin complex 1 (TORC1) is a homeostatic controller of cell growth that adjusts anabolic and catabolic processes to diverse environmental signals, and aberrant mammalian TORC1 signaling contributes to the progression of human diseases such as cancer and diabetes (Albert and Hall, 2015; Eltschinger and Loewith, 2016; Saxton and Sabatini, 2017)
Rag GTPase heterodimers stimulate TORC1 when they contain GTP-loaded Gtr1/RagA/B and GDP-loaded Gtr2/RagC/D, a configuration that is promoted in part by the GTPase activating protein (GAP) complex Lst4-Lst7 that acts on Gtr2 or the orthologous FNIP1/2-Folliculin (FLCN) complex that acts on RagC/D (Peli-Gulli et al, 2015; Petit et al, 2013; Tsun et al, 2013)
To address the mechanistic basis of this dynamic regulation of the Lst4-Lst7 complex localization, we initially studied the potential role in this process of the unstructured loop within the DENN domain of Lst4, which splits the Lst7-interacting DENN domain of Lst4 into two halves (Pacitto et al, 2015) (Figure 1A)
Summary
Amino acids activate Rag GTPaseTORC1 signaling in part through the conserved Lst4-Lst Rag GTPase GAP complex. Peli-Gulli et al show that the Lst4-Lst module is a direct TORC1 target and key node of a feedback mechanism that adjusts TORC1 activity to amino acid availability. Peli-Gulli et al, 2017, Cell Reports 20, 281–288 July 11, 2017 a 2017 The Author(s).
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