| Autor: |
Cox NJ, Unlu G; Departments of Medicine and Cell and Developmental Biology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States., Bisnett BJ, Meister TR, Condon BM, Luo PM, Smith TJ, Hanna M; Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health , Madison, Wisconsin 53706, United States., Chhetri A, Soderblom EJ; Duke Proteomics and Metabolomics Core Facility, Center for Genomic and Computational Biology, Duke University , Durham, North Carolina 27710, United States., Audhya A; Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health , Madison, Wisconsin 53706, United States., Knapik EW; Departments of Medicine and Cell and Developmental Biology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States., Boyce M |
| Jazyk: |
angličtina |
| Zdroj: |
Biochemistry [Biochemistry] 2018 Jan 09; Vol. 57 (1), pp. 91-107. Date of Electronic Publication: 2017 Dec 15. |
| DOI: |
10.1021/acs.biochem.7b00870 |
| Abstrakt: |
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 SEC23A, an essential COPII component, 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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