Fat storage-inducing transmembrane (FIT or FITM) proteins are related to lipid phosphatase/ phosphotransferase enzymes

Matthew J. Hayes, Vineet Choudhary, Namrata Ojha, John J.H. Shin, Gil Soo Han, George M. Carman, Christopher J.R. Loewen, William A. Prinz, Timothy P. Levine

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Fat storage-inducing transmembrane (FIT or FITM) proteins have been implicated in the partitioning of triacylglycerol to lipid droplets and the budding of lipid droplets from the ER. At the molecular level, the sole relevant interaction is that FITMs directly bind to triacyglycerol and diacylglycerol, but how they function at the molecular level is not known. Saccharomyces cerevisiae has two FITM homologues: Scs3p and Yft2p. Scs3p was initially identified because deletion leads to inositol auxotrophy, with an unusual sensitivity to addition of choline. This strongly suggests a role for Scs3p in phospholipid biosynthesis. Looking at the FITM family as widely as possible, we found that FITMs are widespread throughout eukaryotes, indicating presence in the last eukaryotic common ancestor. Protein alignments also showed that FITM sequences contain the active site of lipid phosphatase/phosphotransferase (LPT) enzymes. This large family transfers phosphate-containing headgroups either between lipids or in exchange for water. We confirmed the prediction that FITMs are related to LPTs by showing that single amino-acid substitutions in the presumptive catalytic site prevented their ability to rescue growth of the mutants on low inositol/high choline media when over-expressed. The substitutions also prevented rescue of other phenotypes associated with loss of FITM in yeast, including mistargeting of Opi1p, defective ER morphology, and aberrant lipid droplet budding. These results suggest that Scs3p, Yft2p and FITMs in general are LPT enzymes involved in an as yet unknown critical step in phospholipid metabolism.

Original languageEnglish (US)
Pages (from-to)88-103
Number of pages16
JournalMicrobial Cell
Volume5
Issue number2
DOIs
StatePublished - Feb 2018

All Science Journal Classification (ASJC) codes

  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Keywords

  • Endoplasmic reticulum retention motif
  • Endoplasmic reticulum stress
  • Lipid biosynthesis enzyme
  • Lipid droplet
  • Remote homology search
  • Type 2 diabetes

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