Significance: Protein disulfide isomerase (PDI) and its homologs have essential roles in the oxidative folding and chaperone-mediated quality control of proteins in the secretory pathway. In this review, the importance of PDI in health and disease will be examined, using examples from the fields of lipid homeostasis, hemostasis, infectious disease, cancer, neurodegeneration, and infertility.
Recent advances: Recent structural studies, coupled with cell biological, biochemical, and clinical approaches, have demonstrated that PDI family proteins are involved in a wide range of physiological and disease processes.
Critical issues: Critical issues in the field include understanding how and why a PDI family member is involved in a given disease, and defining the physiological client specificity of the various PDI proteins when they are expressed in different tissues.
Future directions: Future directions are likely to include the development of new and more specific reagents to study and manipulate PDI family function. The development of conditional mouse models in concert with clinical data will help us to understand the in vivo function of the different PDIs at the organism level. Taken together with advances in structural biology and biochemical studies, this should help us to further understand and modify PDIs' functional interactions.