Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1

Abstract

Mutations in the human N-glycanase 1 (NGLY1) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which NGLY1 and its homologs regulate embryonic development are not known. Here we show that Drosophila Pngl encodes an N-glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of Pngl results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. Pngl mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during Drosophila development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an N-glycanase enzyme.

Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

“…In fact, they showed that chemical inhibition of NGLY1 function potentiates cytotoxicity caused by proteasome inhibition in human cancer cell lines ( Tomlin et al 2017 ), which mirrors the observation in nematodes that png-1 loss-of-function mutants are extremely hypersensitive to proteasome inhibition by bortezomib ( Lehrbach and Ruvkun 2016 ). Jafar-Nejad and colleagues showed that the fly NGLY1/Pngl is required during embryonic and larval development in Drosophila for post-translational processing of Dpp , the fly homolog of the conserved bone morphogen protein (BMP) family ( Galeone et al 2017 ), opening up the possibility that NGLY1 is required for the function of multiple glycoprotein clients.…”

N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity

“…NGLY1 also regulates NFE2L1-mediated mitochondrial function (Kong et al, 2018) and inflammation (Yang et al, 2018). NGLY1's deglycosylation activity was also shown to regulate tissue-specific bone morphogenetic protein (BMP) signaling in a Drosophila model (Galeone et al, 2017). Together, these studies suggest a more diverse direct or indirect role for NGLY1 in cellular signaling, which might explain the wide array of symptoms experienced by NGLY1-deficient patients.…”

Defects in the neuroendocrine axis cause global development delay in aDrosophilamodel of NGLY1 Deficiency

“…In fact, they showed that chemical inhibition of NGLY1 function potentiates cytotoxicity caused by proteasome inhibition in human cancer cell lines (Tomlin, 2017), which mirrors the observation in nematodes that png-1 loss-of-function mutants are extremely hypersensitive to proteasome inhibition by bortezomib (Lehrbach, 2016). Jafar-Nejad and colleagues showed that the fly NGLY1/Pngl is required during embryonic and larval development in Drosophila for post-translational processing of Dpp, the fly homolog of the conserved bone morphogen protein (BMP) family (Galeone, 2017), opening up the possibility that NGLY1 is required for the function of multiple glycoprotein clients.…”