Abstract
Sphingolipids are essential components of eukaryotic membranes, where they serve to maintain membrane integrity. They are important components of membrane trafficking and function in signaling as messenger molecules. Sphingolipids are synthesized de novo from very long-chain fatty acids (VLCFA) and sphingoid long-chain bases, which are amide linked to form ceramide and further processed by addition of various headgroups. Little is known concerning the regulation of VLCFA levels and how cells coordinate their synthesis with the availability of long-chain bases for sphingolipid synthesis. Here we show that Elo2, a key enzyme of VLCFA synthesis, is controlled by signaling of the guanine nucleotide exchange factor Rom2, initiating at the plasma membrane. This pathway controls Elo2 phosphorylation state and VLCFA synthesis. Our data identify a regulatory mechanism for coordinating VLCFA synthesis with sphingolipid metabolism and link signal transduction pathways from the plasma membrane to the regulation of lipids for membrane homeostasis.
Highlights
Sphingolipids are synthesized from very long-chain fatty acids and sphingoid bases
The genetic interaction pattern for rom2⌬ closely resembled those of mutations in early sphingolipid synthesis enzymes, such as Elo2, Sur2, Lcb3, or Elo3 (Fig. 1B) [36]. rom2⌬ deletion resulted in synthetic genetic interactions with lcb3⌬, sur2⌬, dpl1⌬ and ysr3⌬, all encoding enzymes of SL metabolism
Rom2 acts as the GTP exchange factor for the small G-protein Rho1, which in turn regulates the activity of protein kinase C1 (Pkc1) (38 – 40)
Summary
Sphingolipids are synthesized from very long-chain fatty acids and sphingoid bases. Results: Rom controls Elo phosphorylation to regulate very long-chain fatty acid synthesis. As in metazoans, including humans, SL synthesis in yeast occurs in two branches that provide VLCFAs (saturated fatty acids containing 20 –26 carbon atoms) and sphingoid long-chain bases These two components are joined to form ceramides, which gain headgroups consisting of inositol phosphate and mannose to form complex sphingolipids [11] (Fig. 1A). We utilized a combination of yeast genetics and quantitative mass spectrometry to unravel important regulation of Elo, one of two elongases catalyzing the first and rate-limiting step of VLCFA synthesis [27, 28]
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