Ero1, diabetes, and the degeneracy of oxidative folding pathways

Published on: Author: Colin Thorpe

In a mouse

In a far-reaching study published in the March 22 issue of JCB (Zito et al., 2010), David Ron and coworkers have investigated the biological consequences of disruption of the Ero1α and β isoforms in the mouse – the first such study in a living mammal.  The Ero1 proteins are believed to generate disulfide bonds in eukaryotes in concert with PDI as depicted in this simplified scheme:

Ero1β is particularly abundant in the pancreas, and this paper explores the consequences of a mouse Ero1β disruption on insulin production.  The beta cells of the islets of Langerhans are prodigious generators of proinsulin and are exemplars of the need to closely manage the secretory output of the endoplasmic reticulum and to handle the oxidative stress that the generation of disulfide bonds entails.  Mice homozygous for the Ero1β mutation developed a diabetic phenotype, as would be expected if this oxidase were a significant contributor to disulfide bond generation in proinsulin.

However, Ron and coworkers provide surprising evidence for the presence of  “…hitherto unanticipated, ERO1-independent mechanisms to generate disulfide bonds in mammalian cells.”  For example, immunoglobulin-generating cells contain both the α- and β-Ero1 paralogs and yet the double mutant mouse shows a “surprisingly minor role of ERO1 in oxidative folding …”

This important study reminds us how much more we need to learn about oxidative folding in higher eukaryotes.  A brief discussion of disulfide generation in higher eukaryotes – including a list of additional candidate pathways – may be found in a recent review on the QSOX enzymes [PubMed].

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