Cargo load reduction

Abstract

In eukaryotic cells, most newly synthesized secretory proteins are first translocated into the endoplasmic reticulum (ER) and transit through organelles that constitute a secretory pathway. However, a fraction of them never reach the desired native state. Instead, these proteins misfold in the ER and are retrotranslocated out of this organelle to the cytoplasm, where they are degraded by the ubiquitin- proteasome system (a process called ERassociated degradation). For efficient retrotranslocation, the disulfide bonds of misfolded proteins must be reduced, and on page 569 in this issue, Ushioda et al. (1) report that this reaction is catalyzed by ERdj5, the first dedicated reductase identified in the ER. The most abundant ER oxidoreductase, protein disulfide isomerase (PDI), contains two thioredoxin-like domains Cys-X-X-Cys (CXXC, where X is another, but not any, amino acid), and can make (oxidize), break (reduce), and isomerize disulfide bonds, depending on reaction conditions (2). In principle, PDI can do the reductase job as well as ERdj5 (3).