TOR complex 2 is a master regulator of plasma membrane homeostasis

Abstract

As first demonstrated in budding yeast (Saccharomyces cerevisiae), all eukaryotic cells contain two, distinct multi-component protein kinase complexes that each harbor the TOR (Target Of Rapamycin) polypeptide as the catalytic subunit. These ensembles, dubbed TORC1 and TORC2, function as universal, centrally important sensors, integrators, and controllers of eukaryotic cell growth and homeostasis. TORC1, activated on the cytosolic surface of the lysosome (or, in yeast, on the cytosolic surface of the vacuole), has emerged as a primary nutrient sensor that promotes cellular biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane, plays a major role in maintaining the proper levels and bilayer distribution of all plasma membrane components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins). This article surveys what we have learned about signaling via the TORC2 complex, largely through studies conducted in S. cerevisiae. In this yeast, conditions that challenge plasma membrane integrity can, depending on the nature of the stress, stimulate or inhibit TORC2, resulting in, respectively, up-regulation or down-regulation of the phosphorylation and thus the activity of its essential downstream effector the AGC family protein kinase Ypk1. Through the ensuing effect on the efficiency with which Ypk1 phosphorylates multiple substrates that control diverse processes, membrane homeostasis is maintained. Thus, the major focus here is on TORC2, Ypk1, and the multifarious targets of Ypk1 and how the functions of these substrates are regulated by their Ypk1-mediated phosphorylation, with emphasis on recent advances in our understanding of these processes.

The fungal pathogen Cryptococcus neoformans adapts to the host environment through TOR-mediated remodeling of phospholipid asymmetry

“…In S. cerevisiae, TOR-Ypk1 also regulates the function of phospholipid flippases responsible for maintaining the asymmetric distribution of PS and PE at the plasma membrane (30,36). Our data suggests that the TOR-Ypk1 axis functions differently in C. neoformans compared to S. cerevisiae.…”

“…Our work has shed light on the role of the TOR pathway in maintaining lipid homeostasis at host CO2 concentrations in C. neoformans. Previous studies in S. cerevisiae (36) as well as in C. neoformans (37) have shown that TOR acts through its target Ypk1 to regulate both phospholipid asymmetry at the plasma membrane and sphingolipid biosynthesis. The ypk1∆ mutant is highly sensitive to CO2, indicating that this arm of the TOR pathway is also critical to high CO2 adaptation.…”

LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans

“…As reduced LPD-3 activity results in impaired ER-to-PM phospholipid trafficking, a lipid homeostatic mechanism is likely triggered to up-regulate sphingolipids in lpd-3 mutants. 26 Given reported sphingolipid modulation of mTOR signaling and longevity, 41 – 43 we next explored the link of hexaceramide biosynthetic enzyme HYL-1 to ins-7 . We found that hyl-1 RNAi led to a strong suppression of ins-7 p∷INS-7∷GFP in lpd-3 mutants ( Figure 2B ).…”

The Extracellular Matrix of Yeasts: A Key Player in the Microbial Biology Change of Paradigm

“…When these are flattened, the associated TORC effectors Slm1 and Slm2 are released and TORC2 is activated, which operates as a master regulator of membrane and wall-related processes [152]. TORC2 controls membrane and protein homeostasis [144,153], including the synthesis of sphingolipids and cytoskeleton reorga-nization which is also indispensable for polarization and invasion, as well as differentiation into pseudo or true hyphae. But maybe more important is that TORC2 and the ESCRT complex [154] are functionally related in the dependence of calcineurin [155].…”