Abstract
Our understanding of sphingolipid metabolism and functions in the baker's yeast Saccharomyces cerevisiae has progressed substantially in the past 2 years. Yeast sphingolipids contain a C26-acyl moiety, all of the genes necessary to make these long-chain fatty acids have been identified, and a mechanism for how chain length is determined has been proposed. Advances in understanding how the de novo synthesis of ceramide and complex sphingolipids is regulated have been made, and they demonstrate that the Target Of Rapamycin Complex 2 (TORC2) controls ceramide synthase activity. Other work shows that TORC2 regulates the level of complex sphingolipids in a pathway using the Slm1 and Slm2 proteins to control the protein phosphatase calcineurin, which regulates the breakdown of complex sphingolipids. The activity of Slm1 and Slm2 has also been shown to be regulated during heat stress by phosphoinositides and TORC2, along with sphingoid long-chain bases and the Pkh1 and Pkh2 protein kinases, to control the actin cytoskeleton, the trafficking of nutrient transporters, and cell viability. Together, these results provide the first molecular insights into understanding previous genetic interaction data that indicated a connection between sphingolipids and the TORC2 and phosphoinositide signaling networks. This new knowledge provides a foundation for greatly advancing our understanding of sphingolipid biology in yeast.
Highlights
Our understanding of sphingolipid metabolism and functions in the baker’s yeast Saccharomyces cerevisiae has progressed substantially in the past 2 years
The common baker’s yeast Saccharomyces cerevisiae has served in many ways to foster our understanding of sphingolipid metabolism and functions, beginning with the early work of Herbert Carter and his students in the 1950s and early 1960s, who played seminal roles in characterizing sphingolipid long-chain bases (LCBs) [6]. This was followed by elucidation of the types of complex sphingolipids found in yeast cells and their route of synthesis by Lester and colleagues
This review describes and integrates advances in understanding the sphingolipid metabolism and functions of S. cerevisiae during the past 2 years and focuses on the role of LCBs in signal transduction pathways that regulate growth, responses to stress, heat stress, exocytosis of plasma membrane proteins, endocytosis, and actin cytoskeleton dynamics
Summary
Sphingolipids contain an LCB, a fatty acid, and a polar head group. The LCBs in yeast are dihydrosphingosine (DHS; sphinganine) and its 4-hydroxy derivative, phytosphingosine (PHS; 4-hydroxysphinganine). The actual molecular mechanism will require further work to determine whether Ypk directly phosphorylates a subunit of ceramide synthase to govern enzyme activity or whether some other Ypk substrate regulates the activity Another interesting finding involved calcineurin, an evolutionarily conserved Ca21/calmodulin-regulated protein phosphatase that downregulates cellular processes controlled by TORC2, including the synthesis of complex sphingolipids (see below). Aronova et al [61] speculated that DHS and PHS act in a feed-forward manner to coregulate Ypk along with TORC2, thereby controlling ceramide synthase activity and the flux of LCBs that are incorporated into ceramides and complex sphingolipids (Fig. 2) These studies in yeast begin to reveal how cells promote ceramide and sphingolipid synthesis when conditions favor growth and how they reduce synthesis when stresses threaten cells and impede growth. The rate of de novo LCB synthesis in yeast is at least partially controlled by the rate of serine uptake
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