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

Antonio Galeone,Seung Yeop Han,Chengcheng Huang,Tadashi Suzuki,Hamed Jafar-Nejad,Akira Hosomi

doi:10.7554/elife.27612

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.

Highlights

NGLY1 (N-glycanase 1) encodes an evolutionarily conserved enzyme that catalyzes the cleavage of N-glycans from glycoproteins (Suzuki et al, 2000)
To further examine the degree of conservation between fly Pngl and its mammalian homologs, we used FC31-mediated transgenesis (Bischof et al, 2007; Venken et al, 2006) to generate transgenic flies capable of overexpressing wild-type (WT) human NGLY1 or the NGLY1-DR402 mutant, a single amino acid in-frame deletion identified in an NGLY1 deficiency patient (Enns et al, 2014), and asked whether they can rescue the homozygous lethality of Pnglex14 and Pnglex18
It has previously been shown that bone morphogenetic protein (BMP) signaling uses a paracrine/autocrine loop in the visceral mesoderm (VM) to sustain and increase the expression of Dpp in parasegment 3 (PS3) and PS7 of embryonic VM

Summary

Introduction

NGLY1 (N-glycanase 1) encodes an evolutionarily conserved enzyme that catalyzes the cleavage of N-glycans from glycoproteins (Suzuki et al, 2000). Whole-genome and -exome sequencing has recently resulted in the identification of NGLY1 mutations in patients with an autosomal recessive developmental disorder called NGLY1 deficiency (Caglayan et al, 2015; Enns et al, 2014; Heeley and Shinawi, 2015; Need et al, 2012). NGLY1-deficient patients show a host of phenotypes including global developmental delay, movement disorder, hypotonia, absent tears, peripheral neuropathy, constipation, and small feet and hands (Enns et al, 2014; Lam et al, 2017). A recent study has provided strong evidence that in C. elegans, a transcription factor called SKN-1 (homolog to mammalian NFE2L1/2) needs to be retrotranslocated from ER to cytoplasm by ERAD machinery and deglycosylated by NGLY1 (PNG-1 in worms) to function properly (Lehrbach and Ruvkun, 2016).

Methods

Results

Conclusion