Feedback Inhibition of the Rag GTPase GAP Complex Lst4-Lst7 Safeguards TORC1 from Hyperactivation by Amino Acid Signals

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Marie-Pierre Péli-Gulli, Serena Raucci, Zehan Hu, Jörn Dengjel, Claudio De Virgilio
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 as a TORC1 target and key node of a homeostatic mechanism that adjusts TORC1 activity to the availability of amino acids.

Graphical abstract

Teaser

Amino acids activate Rag GTPase-TORC1 signaling in part through the conserved Lst4-Lst7 Rag GTPase GAP complex. Here, Péli-Gulli et al. show that the Lst4-Lst7 module is a direct TORC1 target and key node of a feedback mechanism that adjusts TORC1 activity to amino acid availability.


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