Feedback controls between TORC1/TORC2 signaling pathways and tRNA modification by Elongator in Schizosaccharomyces pombe

Abstract

Elongator is a conserved 6-subunit complex involved in the post-transcriptional modification of the anticodon of a subset of tRNAs. The catalytic subunit of this complex, Elp3, catalyzes the early step in the formation of the mcm5, mcm5s2 and ncm5 modifications of a uridine present at the wobble position of the anticodon, which was proposed to promote efficient translation by optimizing codon-anticodon recognition.
Our laboratory has recently demonstrated that in fission yeast, Elongator ensures the coordinated expression of functional groups of genes enriched in codons read by the modified tRNAs. Aside of genes implicated in cell cycle regulation, chromatin silencing or medial cortical node, interestingly the TOR signaling pathway was prominent. More precisely, the Elongator complex has been shown to regulate the translation of different components of both TOR pathways, TORC1 and TORC2. In particular, Elongator is important for the expression of activators and repressors of TORC2 and TORC1, respectively. Remarkably, a particular Elongator mutant phenocopies the inhibition of TORC2 and the hyperactivation of TORC1. The fission yeast TORC1 and TORC2 complexes exert opposite controls on cellular growth and cell differentiation in response to several environmental stimuli including nitrogen and amino acids starvation. However, the way their regulation is coordinated is yet to be elucidated. We have performed a new genetic screen aiming at identifying regulators of Elongator, enhanced by TORC2 complex and some repressor of TORC1 complex. Genetic and biochemical results allowed us to conclude that the phosphorylation of S114-Elp4 by Gsk3 (the main effector of TORC2) inhibits the Elongator complex activity. Moreover, as a result of this work we proposed Ppe1 as the phosphatase counteracting Gsk3 and in turn activating Elongator. Finally, we also have provided evidences that Elongator impacts the TOR activity and is required for efficient shifting from TORC1 to TORC2 activation (and vice versa) during change in nitrogen source.
Taken together, our data indicate that feedback regulations between TORC1/2 and Elongator are pivotal controlling the nutrient dependent balance between cell growth and differentiation.

Date of Award	22 Jun 2017
Original language	English
Awarding Institution	University of Namur
Supervisor	Damien Hermand (Supervisor), Jean-Pierre Gillet (President), Alain Chariot (Jury), Anna-Maria Marini (Jury) & Helmlinger Dominique (Jury)