The Physiological Functions of Mammalian Endoplasmic Oxidoreductin 1: On Disulfides and More

Abstract

Significance: The oxidative process of disulfide-bond formation is essential for the folding of most secretory and membrane proteins in the endoplasmic reticulum (ER). It is driven by electron relay pathways that transfer two electrons derived from the fusion of two adjacent cysteinyl side chains onto various types of chemical oxidants. The conserved, ER-resident endoplasmic oxidoreductin 1 (Ero1) sulfhydryl oxidases that reduce molecular oxygen to generate an active-site disulfide represent one of these pathways. In mammals, two family members exist, Ero1a and Ero1b. Recent Advances: The two mammalian Ero1 enzymes differ in transcriptional and posttranslational regulation, tissue distribution, and catalytic turnover. A specific protein-protein interaction between either isoform and protein disulfide isomerase (PDI) facilitates the propagation of disulfides from Ero1 via PDI to nascent polypeptides, and inbuilt oxidative shutdown mechanisms in Ero1a and Ero1b prevent excessive oxidation of PDI. Critical Issues: Besides disulfide-bond generation, Ero1a also regulates calcium release from the ER and the secretion of disulfide-linked oligomers through its reversible association with the chaperone ERp44. This review explores the functional repertoire and possible redundancy of mammalian Ero1 enzymes. Future Directions: Systematic analyses of different knockout mouse models will be the most promising strategy to shed new light on unique and tissue-specific roles of Ero1a and Ero1b. Moreover, in-depth characterization of the known physical interactions of Ero1 with peroxidases and PDI family members will help broaden our functional and mechanistic understanding of Ero1 enzymes.

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

“…ERO1a activation of IP3R is thought to be mediated independently of its oxidative ability. It has been hypothesized that ERO1a activates IP3R via the sequestration of Erp44, a negative regulator of IP3R [98]. These findings may support the evidence that autophagy induction in response to fluctuation in the cytosolic Ca 2?…”

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

“…Although PDI is the principal substrate of Ero1a (Inaba et al, 2010;Ramming and Appenzeller-Herzog, 2012), evidence exists that, unlike at steady state (see above), other family members such as ERp57 are also oxidized via Ero1a during early time points of recovery after DTT (when Ero1a is maximally active) (Appenzeller-Herzog et al, 2010). In agreement with this, ERp57 reacquires its steady-state redox distribution within seconds in an Ero1a-dependent manner (Appenzeller-Herzog et al, 2010).…”

Calcium-dependent protein folding in amyotrophic lateral sclerosis

“…Disulfide bond formation is extremely sensitive to a disturbance of the lumenal ER environment. The disulfide bonds are introduced into client proteins by ER resident oxidoreductases, such as the glycosylated flavoprotein Ero1␣, which also regulates the IP3-mediated Ca 2+ release [174][175][176]. Expression of PDI is associated with ER stress and disruption of disulfide bonding leads to induction of the UPR [177].…”