The reversal of thiol oxidation in proteins within the endoplasmic reticulum (ER)
is crucial for protein folding, degradation, chaperone function, and the ER
stress response. Our understanding of this process is generally poor but
progress has been made. Enzymes performing the initial reduction of client
proteins, as well as the ultimate electron donor in the pathway, have been
identified. Most recently, a role for the cytosol in ER protein reduction has been
revealed. Nevertheless, how reducing equivalents are transferred from the
cytosol to the ER lumen remains an open question. We review here why
proteins are reduced in the ER, discuss recent data on catalysis of steps in
the pathway, and consider the implications for redox homeostasis within the
early secretory pathway.