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: To assess the impact of the triple mutant genotype on rate of disulfide bond formation in the ER of secretory cells, we prepared lipopolysaccharide stimulated splenocytes (so-called LPS blasts) from TM, DM, and wild-type animals and compared the rate at which disulfide bonds recovered in the cell-associated pool of immunoglobulin M (IgM) following a pulse of the reducing agent DTT. While a subtle kinetic delay was evident in both mutant samples (and was slightly more conspicuous in the TM compared with the DM cells), this experiment showed that disulfide bond formation proceeded rapidly even in cells deficient in all three ER thiol oxidases, ERO1α, ERO1β, and PRDX4 (Figures 1A and 1B).
Affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK. email@example.com