CHAPTER 3.4: Mechanisms of Oxidative Protein Folding and Thiol-dependent Quality Control: Tales of Cysteines and Cystines

Most secretory proteins contain disulfide bonds. Their formation is catalyzed by endoplasmic reticulum (ER)-resident oxidoreductases and is intimately linked to protein quality control (QC). Intermediates in the process expose reactive cysteines, which act as co-localized determinants for assembly, retention/retrieval and degradation. The efficiency of a cysteine as a QC element depends on its accessibility and local pK_a. Moreover, the stringency of thiol-dependent QC (TDQC) depends on the ER redox poise and can be tuned during development. Through TDQC, cells selectively restrict secretion to mature, oxidized proteins and maintain proteostasis in the ER protein factory. Clients are retained/retrieved via reversible disulfide interchange with oxidoreductases of the ER matrix and with ERp44, a pH-regulated chaperone cycling between the ER and the Golgi. At the more acidic pH of the Golgi, ERp44 exposes its active site and RDEL motif, mediating retrieval of clients. These include oligomeric proteins (e.g. immunoglobulin M, adiponectin) and enzymes acting in the ER but devoid of KDEL motifs (Ero1, Prx4, ERAP1 and FGE/Sumf1). Depending on the levels and activity of protein disulfide isomerase (PDI) and ERp44, these enzymes can progress through the secretory pathway and exert extracellular functions. Thus, TDQC regulates protein secretion and intercellular cross-talk during development and inflammation.