Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation
- University of Milan, Italy
- Baylor College of Medicine, United States
- Biozentrum der Universität Basel, Switzerland
- The Jackson Laboratory, United States
- RIKEN Cluster for Pioneering Research, Japan
- RIKEN Global Research Cluster, Japan
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Funding
Grace Science Foundation (Research grant)
- Tadashi Suzuki
- Aamir Zuberi
- Hamed Jafar-Nejad
National Institutes of Health (R35GM130317)
- Hamed Jafar-Nejad
European Union (H2020-MSCA individual fellowship #844147)
- Antonio Galeone
Private Foundation in Italy (Buzzati-Traverso fellowship)
- Antonio Galeone
Fondazione AIRC per la Ricerca sul Cancro (grant # 20661)
- Thomas Vaccari
Worldwide Cancer Research (grant #18-0399)
- Thomas Vaccari
SNSF Ambizione (PZ00P3_180019)
- Shinya Matsuda
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The mice were maintained in the pathogen-free barrier facilities at Jackson Laboratory (Bar Harbor, ME) and at Baylor College of Medicine (Houston, TX). The studies were conducted in accordance with approved institutional animal care and use committee (IACUC) protocols 99066 (Jackson Laboratory) and AN-6012 (Baylor College of Medicine).
Copyright
© 2020, 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.
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