Tsc3 regulates SPT amino acid choice in Saccharomyces cerevisiae by promoting alanine in the sphingolipid pathway

Jihui Ren, Essa M. Saied, Aaron Zhong, Justin Snider, Christian Ruiz, Christoph Arenz, Lina M. Obeid, Geoffrey D. Girnun, Yusuf A. Hannun

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The generation of most sphingolipids (SPLs) starts with condensation between serine and an activated long-chain fatty acid catalyzed by serine palmitoyltransferase (SPT). SPT can also use other amino acids to generate small quantities of noncanonical SPLs. The balance between serine-derived and noncanonical SPLs is pivotal; for example, hereditary sensory and autonomic neuropathy type I results from SPT mutations that cause an abnormal accumulation of alanine-derived SPLs. The regulatory mechanism for SPT amino acid selectivity and physiological functions of noncanonical SPLs are unknown. We investigated SPT selection of amino acid substrates by measuring condensation products of serine and alanine in yeast cultures and SPT use of serine and alanine in a TSC3 knockout model. We identified the Tsc3 subunit of SPT as a regulator of amino acid substrate selectivity by demonstrating its primary function in promoting alanine utilization by SPT and confirmed its requirement for the inhibitory effect of alanine on SPT utilization of serine. Moreover, we observed downstream metabolic consequences to Tsc3 loss: serine influx into the SPL biosynthesis pathway increased through Ypk1-depenedent activation of SPT and ceramide synthases. This Ypk1-dependent activation of serine influx after Tsc3 knockout suggests a potential function for deoxy-sphingoid bases in modulating Ypk1 signaling.

Original languageEnglish (US)
Pages (from-to)2126-2139
Number of pages14
JournalJournal of Lipid Research
Volume59
Issue number11
DOIs
StatePublished - 2018
Externally publishedYes

Keywords

  • Ceramides
  • De-oxysphingolipids
  • Fatty acid
  • HSAN1
  • Lipid signaling
  • Lipidomics
  • Mass spectrometry
  • Serine palmitoyltransferase
  • Sphingolipids
  • Substrate selectivity
  • Transferase
  • Ypk1

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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