Yeast mating: Ceramide acyl chain length matters?

This article refers to:

A link between very long chain fatty acid elongation and mating-specific yeast cell cycle arrest

The distinct and evolutionarily conserved lipid compositions of cellular organelles underscore the importance of these molecules in determining organellar identity and function. The sphingolipids are important for determining the physical properties of membranes and for directly or indirectly regulating the function of membrane proteins. They are also potent signaling molecules that regulate a host of critical cellular processes. The ceramides, which form the backbone of the complex sphingolipids consist of a fatty acid (FA) joined in amide linkage to a long-chain base (LCB). They comprise a family of hundreds of closely related molecules, distinguished by small structural differences in acyl chain length and number and position of double bonds and hydroxylations in the FA and LCB moieties. The results reported by Nickel's and colleagues in this issue of Cell Cycle support a growing body of evidence indicating that these structural differences can significantly impact function.¹

The majority of fatty acids found in cellular lipids have chain lengths of 16 or 18 carbons, but cells also contain very long chain fatty acids (VLCFAs, C20 - C36) that are synthesized by the elongation of shorter fatty acids by ER-associated complexes of enzymes known as the elongases.² VLCFAs are found predominantly in the ceramide backbone of the sphingolipids where they confer unique physical properties to membranes including an increased propensity to localize to membrane domains involved in organizing the components of signaling pathways.³ However, despite the fact that they are essential for the viability of eukaryotic cells, the precise biological functions of the VLCFAs are poorly understood. Mammals have 6 ceramide synthases that generate ceramides with diverse acyl chain lengths, but the 2 ceramide synthases in yeast both generate C26-containing-ceramides. In a previous study, Nickels and colleagues showed that ceramides are required for yeast mating.⁴ Here they report that the VLCFAs are critical for yeast mating, providing important new insight into potential physiological roles of these essential fatty acids.

As for de novo FA synthesis, FA elongation requires condensation of malonyl-CoA with the growing acyl chain, followed by a reduction, dehydration and additional reduction to increase chain length by 2 carbons per cycle. There are 3 yeast genes (ELO1–3) that encode condensing enzymes with distinct substrate specificities.⁵ Elo1 elongates C12-C16 FAs to C16/18 and is functionally redundant with the Fasp complex that catalyzes de novo FA synthesis, but Elo2 and Elo3 are required for VLCFA synthesis and the elo2Δelo3Δ double mutants are inviable. The elo2Δ and elo3Δ single mutants are viable, but deficient in VLCFA synthesis providing the opportunity to investigate the importance of the VLCFAs in yeast mating, a process that is initiated by pheromone binding to a cognate G-protein coupled receptor.

Elegant genetic, biochemical and imaging studies showed that cells lacking Elo2 or Elo3 are defective in all stages of mating including the formation of the polarized shmoo projections, G1 cell cycle arrest, and expression of mating type specific genes. These processes are dependent upon a MAP kinase signaling pathway that is activated by the G-protein-coupled pheromone receptor suggesting the receptor is uncoupled from the MAP kinase signaling cascade in the elo mutants. Indeed, the data indicate this is the case and that uncoupling arises from failure to properly localize Ste5, a scaffolding protein that nucleates MAP kinase clustering and signal initiation. Upon pheromone treatment, Ste5 normally translocates from the nucleus and becomes tethered to the plasma membrane, but Ste5 does not properly relocalize in the elo mutants. Previous studies have shown that both plasma membrane tethering and signaling by Ste5 depend on its binding to PIP₂.^6,7 Interestingly, the elo mutants display reduced mobilization of PIP₂ to the plasma membrane suggesting that VLCFAs are important for PIP₂ dependent tethering and activation of Ste5. Additional studies are needed to elucidate the role of the VLCFAs in PIP₂ mobilization, but it is clear that VLCFA deficiency impacts Ste5 localization and thereby impairs mating specific MAP kinase signaling. Based on previous studies showing that yeast mating is ceramide dependent,⁴ it seems likely that VLCFA-containing ceramides or complex sphingolipids create a specific membrane environment that is important for organizing the mating specific MAPK signaling cascade. It will be interesting to determine whether VLCFAs are involved in GPCR-mediated signaling processes in higher eukaryotes.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.