1. Developmental Biology

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

  1. Antonio Galeone
  2. Seung Yeop Han
  3. Chengcheng Huang
  4. Akira Hosomi
  5. Tadashi Suzuki
  6. Hamed Jafar-Nejad  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. RIKEN Global Research Cluster, Japan
https://doi.org/10.7554/eLife.27612
Share this article
Cite this article
  1. Antonio Galeone
  2. Seung Yeop Han
  3. Chengcheng Huang
  4. Akira Hosomi
  5. Tadashi Suzuki
  6. Hamed Jafar-Nejad
(2017)
Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1
eLife 6:e27612.
https://doi.org/10.7554/eLife.27612
  2. Download BibTeX
  3. Download .RIS

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.

Article and author information

Author details

  1. Antonio Galeone

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Seung Yeop Han

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Chengcheng Huang

    Glycometabolome Team, RIKEN Global Research Cluster, Saitama, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Akira Hosomi

    Glycometabolome Team, RIKEN Global Research Cluster, Saitama, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Tadashi Suzuki

    Glycometabolome Team, RIKEN Global Research Cluster, Saitama, Japan
    Competing interests
    The authors declare that no competing interests exist.

  6. Hamed Jafar-Nejad

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    hamedj@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6403-3379

Funding

Grace Wilsey Foundation (Research Grant)

  • Tadashi Suzuki
  • Hamed Jafar-Nejad

National Institutes of Health (R01GM084135 R01DK109982)

  • Hamed Jafar-Nejad

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Version history

  1. Received: April 8, 2017
  2. Accepted: August 3, 2017
  3. Accepted Manuscript published: August 4, 2017 (version 1)
  4. Version of Record published: September 14, 2017 (version 2)

Copyright

© 2017, Galeone et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,397
    views
  • 449
    downloads
  • 48
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Antonio Galeone
  2. Seung Yeop Han
  3. Chengcheng Huang
  4. Akira Hosomi
  5. Tadashi Suzuki
  6. Hamed Jafar-Nejad
(2017)
Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1
eLife 6:e27612.
https://doi.org/10.7554/eLife.27612

Share this article

https://doi.org/10.7554/eLife.27612

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Developmental Biology

    Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation

    Antonio Galeone, Joshua M Adams ... Hamed Jafar-Nejad
    Research Advance Updated

    During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzyme N-glycanase 1 (NGLY1) is proposed to remove N-glycans from misfolded N-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulates Drosophila BMP signaling in a tissue-specific manner (Galeone et al., 2017). Here, we establish the Drosophila Dpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress and prompts the ER recruitment of NGLY1. The ER-associated NGLY1 then deglycosylates misfolded BMP4 molecules to promote their retrotranslocation and proteasomal degradation, thereby allowing properly-folded BMP4 molecules to proceed through the secretory pathway and activate signaling in other cells. Our study redefines the role of NGLY1 during ERAD and suggests that impaired BMP4 signaling might underlie some of the NGLY1 deficiency patient phenotypes.

    1. Developmental Biology

    Signaling: Enzymatic insights into an inherited genetic disorder

    Liping Zhang, Kelly G Ten Hagen
    Insight

    Mutations in an enzyme involved in protein degradation affect a signaling pathway that stimulates the development of the digestive tract.

    1. Developmental Biology

    Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis

    Amandine Jarysta, Abigail LD Tadenev ... Basile Tarchini
    Research Article

    Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, and GNAO proteins, but may also induce unrelated defects. Here, we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner G protein signaling modulator 2 (GPSM2), whereas GNAI1 and GNAO are not detected. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the sub-cellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: (1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and (2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.