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Chem Biol. 2015 Oct 22;22(10):1301-12. doi: 10.1016/j.chembiol.2015.09.006.

XBP1s Links the Unfolded Protein Response to the Molecular Architecture of Mature N-Glycans.

Author information

1
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
2
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
3
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: mshoulde@mit.edu.

Abstract

The molecular architecture of the mature N-glycome is dynamic, with consequences for both normal and pathologic processes. Elucidating cellular mechanisms that modulate the N-linked glycome is, therefore, crucial. The unfolded protein response (UPR) is classically responsible for maintaining proteostasis in the secretory pathway by defining levels of chaperones and quality control proteins. Here, we employ chemical biology methods for UPR regulation to show that stress-independent activation of the UPR's XBP1s transcription factor also induces a panel of N-glycan maturation-related enzymes. The downstream consequence is a distinctive shift toward specific hybrid and complex N-glycans on N-glycoproteins produced from XBP1s-activated cells, which we characterize by mass spectrometry. Pulse-chase studies attribute this shift specifically to altered N-glycan processing, rather than to changes in degradation or secretion rates. Our findings implicate XBP1s in a new role for N-glycoprotein biosynthesis, unveiling an important link between intracellular stress responses and the molecular architecture of extracellular N-glycoproteins.

PMID:
26496683
PMCID:
PMC4621487
DOI:
10.1016/j.chembiol.2015.09.006
[Indexed for MEDLINE]
Free PMC Article

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