Journal
JOURNAL OF CELL BIOLOGY
Volume 203, Issue 4, Pages 615-627Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201307185
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Funding
- Terry Fox Foundation/Research Institute (New Investigator Award)
- Terry Fox Foundation/Research Institute (New Frontiers Research Program) [PPG09-020005]
- Terry Fox Foundation/Research Institute (Strategic Initiative for Excellence in Radiation Research for the 21st Century [EIRR21] at the Canadian Institutes of Health Research [CIHR])
- Dutch Science Foundation [NWO VENI 916.56.015, NWO ECHO 700.54.013]
- Dutch Cancer Society [KWF UM-2008-4068]
- Princess Margaret Cancer Foundation
- Ontario Institute for Cancer Research
- Government of Ontario
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
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Most proteins destined for the extracellular space require disulfide bonds for folding and stability. Disulfide bonds are introduced co- and post-translationally in endoplasmic reticulum (ER) cargo in a redox relay that requires a terminal electron acceptor. Oxygen can serve as the electron acceptor in vitro, but its role in vivo remains unknown. Hypoxia causes ER stress, suggesting a role for oxygen in protein folding. Here we demonstrate the existence of two phases of disulfide bond formation in living mammalian cells, with differential requirements for oxygen. Disulfide. bonds introduced rapidly during protein synthesis can occur without oxygen, whereas those introduced during post-translational folding or isomerization are oxygen dependent. Other protein maturation processes in the secretory pathway, including ER-localized N-linked glycosylation, glycan trimming, Golgi-localized complex glycosylation, and protein transport, occur independently of oxygen availability. These results suggest that an alternative electron acceptor is available transiently during an initial phase of disulfide bond formation and that post-translational oxygen-dependent disulfide bond formation causes hypoxia-induced ER stress.
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