Human Homologues of LAG1 Reconstitute Acyl-CoA-dependent Ceramide Synthesis in Yeast*

By I. Guillas, J. Jiang, Christine Vionnet, C. Roubaty, Danièle Uldry, R. Chuard, Jinqing Wang, S. Jazwinski, A. Conzelmann. 2003

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Lag1p and Lac1p are two highly homologous membrane proteins of the endoplasmic reticulum. lag1Δ lac1Δ double mutants in Saccharomyces cerevisiae lack an acyl-CoA-dependent ceramide synthase and are either very sick or nonviable, depending on the genetic background. LAG1 and LAC1 are members of a large eukaryotic gene family that shares the Lag1 motif, and some members of this family additionally contain a DNA-binding HOX homeodomain. Here we show that several human LAG1 homologues can rescue the viability of lag1Δ lac1Δ yeast cells and restore acyl-CoA-dependent ceramide and sphingolipid biosynthesis. When tested in a microsomal assay, Lac1p and Lag1p had a strong preference for C26:0-CoA over C24:0-CoA, C20-CoA, and C16-CoA, whereas some human homologues preferred C24:0-CoA and CoA derivatives with shorter fatty acids. This suggests that LAG1 proteins are related to substrate recognition and to the catalytic activity of ceramide synthase enzymes. CLN8, another human LAG1 homologue implicated in ceroid lipofuscinosis, could not restore viability to lag1Δ lac1Δ yeast mutants.

Subfields: Biochemistry, Molecular Biology, Physiology

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Citations in the corpus

Mammalian Ceramide Synthases (2010, background): “CerS were originally known as Lass (Longevity Assurance) genes based on their homology to the yeast protein, longevity assurance gene-1 (LAG1p) (8-10), but were renamed upon their biochemical characterization (7).”
Long‐chain ceramide is elevated in presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes (2008, background): “Among the six known isoenzymes, lass 2 and 4 are specific for the biosynthesis of C18, C20, and C24 ceramide (Guillas et al., 2003; Pewzner-Jung et al., 2006; Riebeling et al., 2003).”
Antiapoptotic roles of ceramide‐synthase‐6‐generated C16‐ceramide via selective regulation of the ATF6/ CHOP arm of ER‐stress‐response pathways (2010, background): “Recently, human dihydro(dh)ceramide synthases 1-6, dh-CerS1-6, identified as yeast homologues of the longevity assurance gene 1-6 (LASS1-6), have been discovered (5, 6).”
Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2 (2008, unknown): “…for stearoyl-CoA in mammalian cells (Venkataraman et al. 2002), we cannot rule out the possibility that the low amounts of CerS1 expressed in white matter might be involved in synthesis of VLCFA-sphingolipids, since in yeast, CerS1 can induce synthesis of C26-ceramide (Guillas et al. 2003).”
Lip1p: a novel subunit of acyl‐CoA ceramide synthase (2005, methodology): “Since human homologs of LAC1 and LAG1 have been recently isolated and can complement the lac1 and lag1 mutations (Venkataraman et al, 2002; Guillas et al, 2003; Riebeling et al, 2003), it would be surprising if no functional homologs of Lip1p were found.”