Two Mammalian Longevity Assurance Gene (LAG1) Family Members, trh1 and trh4, Regulate Dihydroceramide Synthesis Using Different Fatty Acyl-CoA Donors*

By C. Riebeling, J. Allegood, E. Wang, Alfred H. Merrill Jr., A. Futerman. 2003

297 citations recorded by the source corpus.

Overexpression of upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene (LAG1), selectively induces the synthesis of stearoyl-containing sphingolipids in mammalian cells (Venkataraman, K., Riebeling, C., Bodennec, J., Riezman, H., Allegood, J. C., Sullards, M. C., Merrill, A. H. Jr., and Futerman, A. H. (2002) J. Biol. Chem. 277, 35642–35649). Gene data base analysis subsequently revealed a new subfamily of proteins containing the Lag1p motif, previously characterized as translocating chain-associating membrane (TRAM) protein homologs (TRH). We now report that two additional members of this family regulate the synthesis of (dihydro)ceramides with specific fatty acid(s) when overexpressed in human embryonic kidney 293T cells. TRH1 or TRH4-overexpression elevated [3H](dihydro)ceramide synthesis from l-[3-3H]serine and the increase was not blocked by the (dihydro)ceramide synthase inhibitor, fumonisin B1 (FB1). Analysis of sphingolipids by liquid chromatography-electrospray tandem mass spectrometry revealed that TRH4 overexpression elevated mainly palmitic acid-containing sphingolipids whereas TRH1 overexpression increased mainly stearic acid and arachidic acid, which in both cases were further elevated upon incubation with FB1. A similar fatty acid specificity was obtained upon analysis of (dihydro)ceramide synthase activity in vitro using various fatty acyl-CoA substrates, although in a FB1-sensitive manner. Moreover, in homogenates from TRH4-overexpressing cells, sphinganine, rather than sphingosine was the preferred substrate, whereas no preference was seen in homogenates from TRH1-overexpressing cells. These findings lend support to our hypothesis (Venkataraman, K., and Futerman, A. H. (2002) FEBS Lett. 528, 3–4) that Lag1p family members regulate (dihydro)ceramide synthases responsible for production of sphingolipids containing different fatty acids.

Subfields: Biochemistry, Molecular Biology

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Citations in the corpus

Mammalian Ceramide Synthases (2010, methodology): “CerS5 [also known as LASS5 or TRH4 (10)] has been extensively studied, perhaps due to its robust activity and due to its ability to synthesize C16-ceramide, which is often considered to be an important proapoptotic ceramide.”
The complex life of simple sphingolipids (2004, background): “In this short review, we discuss some of this complexity, particularly with respect to one class of membrane lipids—the sphingolipids—which were originally named by J.L.W. Thudichum in 1884 owing to their enigmatic nature.”
An overview of sphingolipid metabolism: from synthesis to breakdown (2010, background): “Cers5 and CerS6 both prefer palmitoyl CoA as substrates and generate predominantly C16-ceramide species [22], [23].”
Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase 3 in colon cancer cells (2009, unknown): “…A uthor M anuscript Exogenous CerS6 localizes primarily to the perinuclear region Ceramide synthases have been identified as proteins that localize to the endoplasmic reticulum (Kitatani et al., 2006; Mizutani et al., 2005; Riebeling et al., 2003; Senkal et al., 2007; Venkataraman et al., 2002).”
CERAMIDE SYNTHASE 1 IS REGULATED BY PROTEASOMAL MEDIATED TURNOVER (2009, background): “This is interesting because there are mixed reports regarding CerS1 expression in lung cells [8,11].”
Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants (2006, background): “Only one cDNA conferred CTL recognition: the Lass5 gene (also known as Trh4 ), encoding an ER-membrane spanning protein that is a member of the TRAM, LAG1 and CLN8 (TLC) family of fatty-acid regulator”
Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. (2007, methodology): “Ceramide synthase primers used to quantify mRNA levels were previously described (Riebeling et al., 2003).”
Roles of bioactive sphingolipids in cancer biology and therapeutics. (2008, background): “…factor 1 (UOG1) (Lee, 1991; Venkataraman et al., 2002), demonstrated that it specifically regulates the synthesis of C18-ceramide with a high degree of fatty-acid chain length specificity (Venkataraman et al., 2002; Riebeling et al., 2003; Mizutani et al., 2005; Kageyama-Yahara and Riezman, 2006).”