ZFIN ID: ZDB-PUB-171122-13
Dynamic glycosylation governs the vertebrate COPII protein trafficking pathway
Cox, N.J., Unlu, G., Bisnett, B.J., Meister, T.R., Condon, B., Luo, P.M., Smith, T.J., Hanna, M., Chhetri, A., Soderblom, E.J., Audhya, A., Knapik, E.W., Boyce, M.
Date: 2017
Source: Biochemistry   57(1): 91-107 (Journal)
Registered Authors: Knapik, Ela W., Unlu, Gokhan
Keywords: none
MeSH Terms:
  • Acetylglucosamine/metabolism*
  • Acylation
  • Animals
  • COP-Coated Vesicles/metabolism*
  • Cell Line
  • Collagen/metabolism
  • Craniofacial Abnormalities/metabolism
  • Disease Models, Animal
  • Glycosylation
  • Humans
  • Organelles/metabolism
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Protein Transport
  • Vertebrates
  • Vesicular Transport Proteins/chemistry
  • Vesicular Transport Proteins/genetics
  • Vesicular Transport Proteins/metabolism*
  • Zebrafish
PubMed: 29161034 Full text @ Biochemistry
The COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic or pathological cues. Several COPII proteins are modified by O-linked β-N-acetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein-protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of the essential COPII component Sec23A are required for its function in human cells and vertebrate development, because mutation of these sites impairs Sec23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway.