Interplays of AMPK and TOR in Autophagy Regulation in Yeast

Abstract

Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology.

Keywords: S. pombe; ageing; caloric restriction; fission yeast; lifespan; mTOR; rapamycin.

Figure 1

Schematic showing TORC1 and TORC2 complexes in fission yeast and the main processes they control.

Figure 2

Ssp1-Ssp2 signalling integrates environmental cues and cellular ATP levels with TORC1 (mainly Tor2-containing in S. pombe) and TORC2 (mainly Tor1-containing in S. pombe) signalling. Nutrient and environmental stresses activate Ssp1 which activates Ssp2 to drive cells trough mitosis via inhibition of TORC1. Ssp1 also suppresses Srk1 stability to facilitate progression into mitosis following a transient Sty1-mediated cell cycle delay. Ssp2 inhibits TORC1 activity, resulting in the activation of the S. pombe Greatwall homologue Ppk18. Ppk18 activates the endosulfine Igo1 which inhibits the PP2A^Pab1 phosphatase and drives cells into mitosis via Cdc25 activation and inhibition of Wee1. Activated Ssp2 is not required for autophagy induction but induces Ght5 hexose transporter expression when glucose levels are low. As glucose activates TORC2, Ssp2 may serve to ensure full activation of Tor1 when glucose availability is limited. Tor1 and Gad8 regulate Ght5 localisation. Gad8 also regulates amino acid transporter localisation and stability via Gsk3-mediated stabilisation of the Pub1 HECT-type E3-ligase. Nitrogen, but not glucose, withdrawal triggers Ght5 degradation. Ssp2, thus, appears to regulate Ght5 expression in response to glucose levels. It remains unclear how TORC1 is inhibited to permit autophagy induction in ssp2Δ mutants. Modulation of TORC2 activity under conditions of nutrient stress may influence autophagy induction. Mutants with decreased TORC2 signalling exhibit increased autophagy induction relative to wildtype cells.