Leucyl-tRNA synthetase controls TORC1 via the EGO complex

Department of Biology, Division of Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerland.
Molecular cell (Impact Factor: 14.02). 03/2012; 46(1):105-10. DOI: 10.1016/j.molcel.2012.02.009
Source: PubMed


The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1-regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. This interaction is necessary and sufficient to mediate leucine signaling to TORC1 and is disrupted by the engagement of Cdc60 in editing mischarged tRNA(Leu). Thus, the EGOC-TORC1 signaling module samples, via the LeuRS-intrinsic editing domain, the fidelity of tRNA(Leu) aminoacylation as a proxy for leucine availability.

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Available from: Claudio De Virgilio, Sep 10, 2014
    • "Another component implicated in amino acid signaling mTORC1 is linked to leucyl-tRNA synthetase (LeuRS). Indeed, it had been demonstrated in two studies that this enzyme charging LEU to its corresponding tRNA, also acted as a leucine sensor in the activation of mTORC1[137,138]. Yet, the regulatory mechanism details differ considerably from one study to the other and complementary works are mandatory to validate for good this possible regulatory component of the mTORC1 signaling pathway. "
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    • "In mammalian cells, these include (1) the pentameric Ragulator complex that tethers Rag heterodimers to the lysosomal membrane and acts as RagA/B GEF (Bar- Peled et al., 2012), (2) the heterotrimeric GATOR1 complex with RagA/B GAP activity (Bar-Peled et al., 2013), and (3) the heterodimeric FNIP-Folliculin complex that functions as RagC/ D GAP (Petit et al., 2013; Tsun et al., 2013). The amino-acidsensitive events upstream of these Rag GTPase regulators are currently poorly understood, but likely involve both lysosomal amino acid sensors, such as the v-ATPase and lysosomal amino acid transporter(s) (Rebsamen et al., 2015; Wang et al., 2015; Zoncu et al., 2011), and cytoplasmic amino acid sensors, such as the leucyl-tRNA synthetase (LeuRS) (Bonfils et al., 2012; Han et al., 2012). Some of the regulatory mechanisms impinging on Rag GTPases have been remarkably conserved throughout evolution . "
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    • "Endogenous membranes of the protein secretory pathway have also emerged as important platforms for Tor signaling. First, all components of the TORC1 complex (Tor1, Tor2, Kog1, Lst8, and Tco89) (Cardenas and Heitman 1995; Kunz et al. 2000; Chen and Kaiser 2003; Wedaman et al. 2003; Reinke et al. 2004; Aronova et al. 2007) as well as TORC1 regulators (EGO complex) (Dubouloz et al. 2005; Gao and Kaiser 2006; Kim et al. 2008; Binda et al. 2009; Bonfils et al. 2012) and downstream effectors, such as the Tap42–Sit4 phosphatase complex and the AGC kinase Sch9 (Yan et al. 2006; Urban et al. 2007) localize to the late endosome and vacuole membranes. Moreover, the Golgi Ca 2+ /Mn 2+ ATPase Pmr1 has been described to negatively regulate TORC1 function (Devasahayam et al. 2006). "
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