Regulation of BMP Signaling by O-GlcNAcylation

Abstract

P P Mad P Tkv Put Dpp P P Mad P Mad P Tkv Put Dpp Put Dpp P P Sax Put Dpp P Sax O Sxc Normal glucose and Sxc Low glucose or no Sxc Extracellular space Cytoplasm Graphical Abstract Moulton et al. p. 2 Summary Precise regulation of signal transduction is critical throughout organismal life, both for embryonic development and for adult homeostasis. To ensure proper spatio-temporal signal transduction, Bone Morphogenetic Protein (BMP) signaling pathways, like all other signaling pathways, are regulated by both agonists and antagonists. Here, we report identification of a previously unrecognized method of signal antagonism for Dpp (Decapentaplegic), a Drosophila BMP family member. We demonstrate that the BMP type I receptor Saxophone (Sax) functions as a Dpp receptor in the Drosophila embryonic epidermis, but that its activity is normally inhibited by the Olinked glycosyltransferase Super sex combs (Sxc). In wild-type embryos, inhibition of Saxophone (Sax) activity in the epidermis marks the BMP type I receptor Thickveins (Tkv) as the sole conduit for Dpp. In contrast, in sxc mutants, the Dpp signal is transduced by both Tkv and Sax, and elevated Dpp signaling induces errors in embryonic development that lead to embryonic death.We also demonstrate that Sax is the O-glycosylated target of Sxc and that O-glycosylation of Sax can be modulated by dietary sugar. Together, these findings link fertility to nutritive environment and point to Sax (activin receptor-like kinase [Alk] 1/2) signaling as the nutrient-sensitive branch of BMP signaling.

A mutant bacterial O-GlcNAcase visualizes a progressive decline of protein O-GlcNAcylation in early Drosophila embryos critical for neurodevelopment

“…The UDP-N-acetylglucosamine pyrophosphorylase Mummy, a key enzyme catalyzes the formation of UDP-GlcNAc, antagonizes the Dpp/BMP signaling 44 . Furthermore O-GlcNAcylation inhibits the Dpp/BMP type I receptor Sax 45 . Our results reveal that at transcriptional level, low O-GlcNAcylation via polycomb repression inhibits the expression of the Dpp/BMP antagonist sog.…”