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. email@example.comShow MeSH
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Mentions: The aforementioned observations indicated that the connective tissue of mice with compromised ER thiol oxidases was defective. To explore this problem, we turned to MEFs, a cell culture model for connective tissue. Immunoblot confirmed the presence of ERO1α and PRDX4 in the control population (ERO1β is not detectable in MEFs, Zito et al., 2010a) and their absence in the DM and TM populations. Levels of the ER chaperones BiP and GRP94 were only minimally elevated in the mutant cells, indicating comparable levels of unfolded protein stress in the ER of MEFs of the three genotypes (Figure 3A).
Affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK. firstname.lastname@example.org