Drosophila α-1,4-glycosyltransferase (α-4GT1) inhibits reaper-mediated apoptosis in the eye

Abstract

In a genetic screen, alpha-4GT1 has been identified as a potential enhancer of Hairless-mediated cell death in the eye of Drosophila. alpha-4GT1 encodes an alpha-1,4-glycosyltransferase, known to catalyze the fifth step in a series of ceramide glycosylation events. As reported for other enzymes involved in the glycosylation of ceramide, alpha-4GT1 is strongly expressed during oogenesis and is deposited maternally in the egg. Moreover, the protein is enriched at cell membranes. Unexpectedly, overexpression of alpha-4GT1 does not enhance Hairless-mediated cell death; instead, Hairless enhancement is caused by an allele of Scutoid present on the alpha-4GT1 chromosome. Interestingly, the downregulation of alpha-4GT1 during eye development amplifies cell death induction by the pro-apoptotic gene reaper. Accordingly, overexpression of alpha-4GT1 represses reaper-induced cell death. Thus, alpha-4GT1 appears to be an inhibitor of apoptosis, as has previously been observed for other ceramide glycosylating enzymes, suggesting that it likewise contributes to ceramide anchoring in the membrane.

Notch ligand activity is modulated by glycosphingolipid membrane composition in Drosophila melanogaster

“…The α4GT1 gene encodes a ubiquituously expressed enzyme predicted to regulate GSL biosynthesis (Chen et al, 2007; Protzer et al, 2009). To investigate the role of the α4GT1 gene in Notch signaling, we generated two molecularly null mutant alleles: the α4GT1 1 allele deletes the first 286 amino acids of the α4GT1 protein, and the α4GT1 2 allele carries a nonsense mutation at K131.…”

Roles of sphingolipids in Drosophila development and disease

“…An a1,4GalNAc-T in flies has also been identified (Protzer et al 2009), in which a specific (but again, not lethal) interaction was discovered with Notch signaling, in a recent study by the Schweisguth group (Hamel et al 2010). Here, Gal4-mediated over-expression of the a1,4GalNAc-T gene was found to suppress the Notch-like phenotype of loss of function in mindbomb (Mib1), an E3 ubiquitin ligase that functions in Notch endocytosis and activation.…”

“…An α1,4GalNAc‐T in flies has also been identified (Protzer et al. 2009), in which a specific (but again, not lethal) interaction was discovered with Notch signaling, in a recent study by the Schweisguth group (Hamel et al.…”

“…GlcT-1 over-expression prevents induction of apoptosis by reaper and grim, and RNAi knockouts in GlcT-1 result in widespread embryonic cell death (Kohyama-Koganeya et al 2004). Likewise, a4GT1 was shown to be an inhibitor of apoptosis in the eye (Protzer et al 2009).…”

Down-regulation of β-1,3-N-acetylglucosaminyltransferase-8 by siRNA inhibits the growth of human gastric cancer

“…numerous reports have demonstrated that glycosyltransferases directly modify carbohydrates on cell surface receptors and cell adhesion molecules, which then promotes or inhibits tumor cell growth. For example, α-4GT1, which encodes α-1,4-glycosyltransferase, appears to be an inhibitor of apoptosis (17). C2GnT-I is an enzyme that acts in the Golgi to modify glycoproteins destined for export to the cell surface, which then interact with the extracellular milieu.…”