Article

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

ABSTRACT

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.

Download full-text

Full-text

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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Beside their main contribution as substrates for protein synthesis, amino acids as signaling molecules could exert some regulatory functions on protein synthesis and/or proteolysis that have been emphasized in a number of recent studies. Several publications have highlighted supplemental roles of those amino acids in protein metabolism as well as in immunity, heat shock response or apoptosis processes. In this way, via their regulatory properties, selected amino acids (like leucine, glutamine, arginine, citrulline or methionine) directly influence the proteome. In this review, we are proposing an overview of the regulation of the proteome by amino acids in mammals. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Proteomics
  • Source
    • "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 . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rag GTPases assemble into heterodimeric complexes consisting of RagA or RagB and RagC or RagD in higher eukaryotes, or Gtr1 and Gtr2 in yeast, to relay amino acid signals toward the growth-regulating target of rapamycin complex 1 (TORC1). The TORC1-stimulating state of Rag GTPase heterodimers, containing GTP- and GDP-loaded RagA/B/Gtr1 and RagC/D/Gtr2, respectively, is maintained in part by the FNIP-Folliculin RagC/D GAP complex in mammalian cells. Here, we report the existence of a similar Lst4-Lst7 complex in yeast that functions as a GAP for Gtr2 and that clusters at the vacuolar membrane in amino acid-starved cells. Refeeding of amino acids, such as glutamine, stimulated the Lst4-Lst7 complex to transiently bind and act on Gtr2, thereby entailing TORC1 activation and Lst4-Lst7 dispersal from the vacuolar membrane. Given the remarkable functional conservation of the RagC/D/Gtr2 GAP complexes, our findings could be relevant for understanding the glutamine addiction of mTORC1-dependent cancers.
    Full-text · Article · Sep 2015 · Cell Reports
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nitrogen catabolite repression (NCR) is the regulatory pathway through which Saccharomyces cerevisiae responds to the available nitrogen status and selectively utilizes rich nitrogen sources in preference to poor ones. Expression of NCR-sensitive genes is mediated by two transcription activators, Gln3 and Gat1, in response to provision of a poorly used nitrogen source or following treatment with the TORC1 inhibitor, rapamycin. During nitrogen excess, the transcription activators are sequestered in the cytoplasm in a Ure2-dependent fashion. Here, we show that Vps components are required for Gln3 localization and function in response to rapamycin treatment when cells are grown in defined yeast nitrogen base but not in complex yeast peptone dextrose medium. On the other hand, Gat1 function was altered in vps mutants in all conditions tested. A significant fraction of Gat1, like Gln3, is associated with light intracellular membranes. Further, our results are consistent with the possibility that Ure2 might function downstream of the Vps components during the control of GATA factor-mediated gene expression. These observations demonstrate distinct media-dependent requirements of vesicular trafficking components for wild-type responses of GATA factor localization and function. As a result, the current model describing participation of Vps system components in events associated with translocation of Gln3 into the nucleus following rapamycin treatment or growth in nitrogen-poor medium requires modification.
    Full-text · Article · Jun 2014 · MicrobiologyOpen
Show more