Mol. Cell 52, 75–86 (2013)

Pathogenic versions of the metalloenzyme copper zinc superoxide dismutase (SOD1) have been detected in the neurodegenerative disorder amyotrophic lateral sclerosis. Recent studies have suggested that mutant forms of SOD1 might contribute to ER stress and subsequent toxicity via interactions with the ER-associated degradation membrane protein derlin-1. Surprisingly, the wild-type form of SOD1 contains a hidden derlin-1 binding site (DBS) that mediates binding under serum-starved conditions. The reintroduction of serum blocks this interaction, but the serum component that modulates SOD1–derlin-1 interactions remained unclear. Homma et al. performed gel filtration chromatography of fetal bovine serum (FBS) fractions to identify the serum component, which was revealed to be inorganic. The authors found that the addition of zinc could disrupt SOD1–derlin-1 interactions through the concealing of the DBS site. Reduction in zinc levels through addition of chelators such as TPEN provoked changes in SOD1 conformation through exposing the DBS, resulting in the upregulation of the ER stress machinery. Finally, activation of the ER stress components PERK and ATF6 decreased protein synthesis and induced the expression of the zinc transporter, ZIP14, respectively. Thus, the SOD1–derlin-1 complex provides a critical link between the cellular responses to ER stress and zinc deficiency.