期刊
MOLECULAR CELL
卷 48, 期 1, 页码 39-51出版社
CELL PRESS
DOI: 10.1016/j.molcel.2012.08.010
关键词
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资金
- Wellcome Trust Principal Research Fellowship
- EU FP7 BetaBat grant [277713]
- NIH grant [DK47119]
- EMBO Fellowship
- EU Marie Curie reintegration grant
- MRC [G0600717] Funding Source: UKRI
- Medical Research Council [G0600717, G0600717B] Funding Source: researchfish
Endoplasmic reticulum (ER) thiol oxidases initiate a disulfide relay to oxidatively fold secreted proteins. We found that combined loss-of-function mutations in genes encoding the ER thiol oxidases ERO1 alpha, ERO1 beta, and PRDX4 compromised the extracellular matrix in mice and interfered with the intracellular maturation of procollagen. These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower procollagen 4-hydroxy-proline content and enhanced cysteinyl sulfenic acid modification of ER proteins. Tissue ascorbic acid content was lower in mutant mice, and ascorbic acid supplementation improved procollagen maturation and lowered sulfenic acid content in vivo. In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H2O2-generating system. Compromised ER disulfide relay thus exposes protein thiols to competing oxidation to sulfenic acid, resulting in depletion of ascorbic acid, impaired procollagen proline 4-hydroxylation, and a noncanonical form of scurvy.
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