Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice.
Bottom Line: 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-hydroxyproline content and enhanced cysteinyl sulfenic acid modification of ER proteins.In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H(2)O(2)-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.
Affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK. firstname.lastname@example.orgShow MeSH
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Mentions: Type I collagen, the abundant species made by MEFs, is synthesized as a precursor, procollagen. The precursor is modified cotranslationally by lumenal proline and lysine hydroxylases, and later trimer-stabilizing disulfide bonds form between the C-terminal propieces. The procollagen trimer traffics rapidly from the ER and is efficiently processed to mature collagen in post-ER compartments (Lamande and Bateman, 1999). Therefore wild-type MEFs have low levels of procollagen. Exposure to brefeldin A (BFA), which interferes with ER trafficking, traps procollagen in the ER and increases its steady-state levels (Figure 4A, lanes 1–4). Both DM and TM MEFs have abnormally elevated steady-state levels of procollagen (Figure 4A). These observations point to a defect in procollagen maturation in the mutant cells.
Affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK. email@example.com