Membrane Contact Sites in Yeast: Control Hubs of Sphingolipid Homeostasis.

Philipp Schlarmann,Kouichi Funato,Atsuko Ikeda

doi:10.3390/membranes11120971

Abstract

Sphingolipids are the most diverse class of membrane lipids, in terms of their structure and function. Structurally simple sphingolipid precursors, such as ceramides, act as intracellular signaling molecules in various processes, including apoptosis, whereas mature and complex forms of sphingolipids are important structural components of the plasma membrane. Supplying complex sphingolipids to the plasma membrane, according to need, while keeping pro-apoptotic ceramides in check is an intricate task for the cell and requires mechanisms that tightly control sphingolipid synthesis, breakdown, and storage. As each of these processes takes place in different organelles, recent studies, using the budding yeast Saccharomyces cerevisiae, have investigated the role of membrane contact sites as hubs that integrate inter-organellar sphingolipid transport and regulation. In this review, we provide a detailed overview of the findings of these studies and put them into the context of established regulatory mechanisms of sphingolipid homeostasis. We have focused on the role of membrane contact sites in sphingolipid metabolism and ceramide transport, as well as the mechanisms that prevent toxic ceramide accumulation.

Highlights

Sphingolipids are important components of cellular membranes that exert various functions, depending on their structural maturation and subcellular localization
As acylceramides are synthesized in the endoplasmic reticulum (ER) and stored with other neutral lipids in lipid droplets (LDs) (Figure 3A), it is possible that acylceramide stored in the LD may be directly transported to the Golgi via LD-Golgi contact sites, and tricalbins may facilitate the delivery of acylceramide from the LD
In addition to the identification of genes involved in sphingolipid synthesis and catabolism and the mechanisms of post-translational regulation of sphingolipid synthesis, through phosphorylation and ubiquitination, some tethers that physically bridge the pairs of organelles at the contact sites have recently been demonstrated to play a role in sphingolipid trafficking

Summary

Introduction

Sphingolipids are important components of cellular membranes that exert various functions, depending on their structural maturation and subcellular localization. Unlike the SPT complex, which depends on Orm1/2 interaction, ceramide synthase and many other key enzymes in sphingolipid biosynthesis are regulated by direct phosphorylation through protein kinases Both the ceramide synthase subunits Lag and Lac are phosphorylated by Ypk to activate ceramide synthesis [58,59]. It was shown that the VLCFA elongase Elo is phosphorylated and inactivated by Mck kinase, a presumed downstream effector of the CWI pathway (Figure 1B), and a model was proposed in which CWI signaling is inactivated in response to perturbed sphingolipid synthesis to de-repress Elo2 [69] This model requires additional investigation, as it remains unclear how signals from the PM are transduced to Elo and how Elo inhibition is coordinated with other CWI functions. The protein phosphatase PP2A, which is activated by ceramides [44], has been proposed to mediate inhibition of Ypk1 [86] or Pkh1/2 [87]

MCSs in Sphingolipid Metabolism

MCSs in Non-Vesicular Transport of Ceramide

MCSs and LDs in Ceramide Lipotoxicity

Findings

Conclusions and Outlook