Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway.

Abstract

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.

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Citation

Published Version (Please cite this version)

10.1021/acs.biochem.7b00870

Publication Info

Cox, Nathan J, Gokhan Unlu, Brittany J Bisnett, Thomas R Meister, Brett M Condon, Peter M Luo, Timothy J Smith, Michael Hanna, et al. (2018). Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway. Biochemistry, 57(1). pp. 91–107. 10.1021/acs.biochem.7b00870 Retrieved from https://hdl.handle.net/10161/19691.

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Scholars@Duke

Smith

Tim Smith

Student
Soderblom

Erik James Soderblom

Associate Research Professor of Cell Biology

Director, Proteomics and Metabolomics Core Facility

Boyce

Michael Scott Boyce

Associate Professor of Biochemistry

The Boyce Lab studies mammalian cell signaling through protein glycosylation. For the latest news, project information and publications from our group, please visit our web site at http://www.boycelab.org or follow us on Twitter at https://twitter.com/BoyceLab.


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