Seipin is involved in the regulation of phosphatidic acid metabolism at a subdomain of the nuclear envelope in yeast

Biochim Biophys Acta. 2015 Nov;1851(11):1450-64. doi: 10.1016/j.bbalip.2015.08.003. Epub 2015 Aug 12.


Yeast Fld1 and Ldb16 resemble mammalian seipin, implicated in neutral lipid storage. Both proteins form a complex at the endoplasmic reticulum-lipid droplet (LD) interface. Malfunction of this complex either leads to LD clustering or to the generation of supersized LD (SLD) in close vicinity to the nuclear envelope, in response to altered phospholipid (PL) composition. We show that similar to mutants lacking Fld1, deletion of LDB16 leads to abnormal proliferation of a subdomain of the nuclear envelope, which is tightly associated with clustered LD. The human lipin-1 ortholog, the PAH1 encoded phosphatidic acid (PA) phosphatase, and its activator Nem1 are highly enriched at this site. The specific accumulation of PA-binding marker proteins indicates a local enrichment of PA in the fld1 and ldb16 mutants. Furthermore, we demonstrate that clustered LD in fld1 or ldb16 mutants are transformed to SLD if phosphatidylcholine synthesis is compromised by additional deletion of the phosphatidylethanolamine methyltransferase, Cho2. Notably, treatment of wild-type cells with oleate induced a similar LD clustering and nuclear membrane proliferation phenotype as observed in fld1 and ldb16 mutants. These data suggest that the Fld1-Ldb16 complex affects PA homeostasis at an LD-forming subdomain of the nuclear envelope. Lack of Fld1-Ldb16 leads to locally elevated PA levels that induce an abnormal proliferation of nER membrane structures and the clustering of associated LD. We suggest that the formation of SLD is a consequence of locally altered PL metabolism at this site.

Keywords: Diacylglycerol; Lipid droplet; Nuclear envelope; Phosphatidate phosphatase; Phosphatidic acid; Saccharomyces cerevisiae; Seipin; Yeast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • GTP-Binding Protein gamma Subunits / deficiency
  • GTP-Binding Protein gamma Subunits / genetics*
  • Gene Expression Regulation, Fungal*
  • Lipid Droplets / drug effects
  • Lipid Droplets / metabolism
  • Lipid Droplets / ultrastructure
  • Lipid Metabolism / drug effects
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics*
  • Mutation
  • Nuclear Envelope / drug effects
  • Nuclear Envelope / genetics
  • Nuclear Envelope / metabolism*
  • Nuclear Envelope / ultrastructure
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oleic Acid / pharmacology
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism
  • Phosphatidic Acids / metabolism*
  • Phosphatidylcholines / metabolism
  • Phosphatidylethanolamine N-Methyltransferase / genetics
  • Phosphatidylethanolamine N-Methyltransferase / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae / ultrastructure
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction


  • GTP-Binding Protein gamma Subunits
  • LDB16 protein, S cerevisiae
  • Mitochondrial Proteins
  • Nem1 protein, S cerevisiae
  • Nuclear Proteins
  • Phosphatidic Acids
  • Phosphatidylcholines
  • Saccharomyces cerevisiae Proteins
  • seipin protein, S cerevisiae
  • Oleic Acid
  • CHO2 protein, S cerevisiae
  • Phosphatidylethanolamine N-Methyltransferase
  • PAH1 protein, S cerevisiae
  • Phosphatidate Phosphatase