Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

PLoS Genet. 2020 Aug 26;16(8):e1008745. doi: 10.1371/journal.pgen.1008745. eCollection 2020 Aug.

Abstract

Sphingolipids are abundant and essential molecules in eukaryotes that have crucial functions as signaling molecules and as membrane components. Sphingolipid biosynthesis starts in the endoplasmic reticulum with the condensation of serine and palmitoyl-CoA. Sphingolipid biosynthesis is highly regulated to maintain sphingolipid homeostasis. Even though, serine is an essential component of the sphingolipid biosynthesis pathway, its role in maintaining sphingolipid homeostasis has not been precisely studied. Here we show that serine uptake is an important factor for the regulation of sphingolipid biosynthesis in Saccharomyces cerevisiae. Using genetic experiments, we find the broad-specificity amino acid permease Gnp1 to be important for serine uptake. We confirm these results with serine uptake assays in gnp1Δ cells. We further show that uptake of exogenous serine by Gnp1 is important to maintain cellular serine levels and observe a specific connection between serine uptake and the first step of sphingolipid biosynthesis. Using mass spectrometry-based flux analysis, we further observed imported serine as the main source for de novo sphingolipid biosynthesis. Our results demonstrate that yeast cells preferentially use the uptake of exogenous serine to regulate sphingolipid biosynthesis. Our study can also be a starting point to analyze the role of serine uptake in mammalian sphingolipid metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / metabolism*
  • Homeostasis
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Serine / metabolism*
  • Sphingolipids / biosynthesis
  • Sphingolipids / metabolism*

Substances

  • Amino Acid Transport Systems, Acidic
  • GNP1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sphingolipids
  • Serine

Grants and funding

Florian Fröhlich is supported by the DFG grant FR 3647/2-1 and the SFB944 (P20) (https://www.dfg.de/). Sergej Limar and André Bogdanowski are supported by the EvoCell Graduate School of the University of Osnabrück. This research was supported by the VILLUM Foundation (VKR023439, C.S.E. veluxfoundations.dk) and the University of Southern Denmark (SDU2020, C.S.E. www.sdu.dk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.