The ancient PDI is a ubiquitous redox chaperone belonging to the thioredoxin oxireductase super family and can reduce (reaction 1), oxidize (reaction 2), and catalyse dithiol-disulfide exchange reactions (i.e., isomerase activities, reaction 3, Figure 1 ). Such broad range of activities overlaps with the chaperone role of PDI that overall performs a housekeeping function in helping to maintain proteins in a more stable conformation. There are around 20 PDI homologues, and the detailed structure and function of eukaryotic PDIs have been covered in recent excellent reviews [4, 5] . The classic mammalian PDI (55 kDa) has several domains ordered as a-b-b -a -c with 2 thioredoxin-like motifs (Trp-Cys-Gly-His-Cys) displayed in the a and a domain [4] [5] [6] (Figure 1 ). PDI is abundant in the ER (∼ 0.5 mM) where the relatively oxidizing conditions at basal level (i.e., GSH/GSSG ratios ∼ 2-3 : 1) favours PDI isomerase/oxidase activity, which is primarily involved in client protein redox folding (reaction 2-3, Figure 1 ). The oxidizing equivalents for this process are driven mainly by the ER thiol-containing oxidase, Ero1 (endoplasmic reticulum oxidase-1), which binds FAD and is in turn re-oxidized via electron transfer to oxygen, generating H 2 O 2 in the process [7] [8] [9] [10] . The H 2 O 2 destiny is elusive, but it can oxidize ER-located peroxiredoxin IV (PrxIV) that is further reduced by PDI that is oxidized in the process [11] . This redox circuit is thought to increase total protein folding and thiol oxidation via Ero1 [11] . However, even in the absence of Ero1, protein folding still occurs, and it is suggested that other oxidases may compensate for redox demand in the ER in some circumstances [12, 13] . Nevertheless, the PDI-Ero1-dependent oxidative activity is balanced to cytosolic glutathione levels suggesting a functional redox interplay between these compartments [12] . PDI reductase activity has been primarily associated to more reducing compartments (i.e., GSH/GSSG ratios ∼ 30-100 : 1), such as those in the vicinity of the plasma membrane [6, 10] . PDI redox versatility is mainly governed by the low pKa of the proximal cysteine on the active N-terminal a domain. Indeed, the lower pKa of 4.5 renders PDI a much better oxidase than thioredoxin, which has a pKa of 7.1 and is mainly a reductase in most neutral pH cell compartments. It should also be noted that PDI functions as a chaperone independently of its redox-active domains as especially required for its ATPase and Ca 2+ activity, although PDI redox motifs still stabilize binding interaction [4, 5, 10] . In the ER, PDI is tightly associated with prolyl-4 hydroxylase (the rate-limiting enzyme for collagen biosynthesis), the Sec61 translocon, and the MHC class I complex (see later). It can be also found as a heterodimer with microsomal triglyceride transfer protein [6, 10] . PDI is a soluble homodimer and does not have a transmembrane domain and, similarly to other ER chaperones, carries the KDEL C-terminal sequence which binds to respective receptors in the COP vesicles that circulate in the ER-Golgi vicinity, recycling proteins back to ER. PDI also undergoes intense intracellular trafficking and is found on the surface of diverse prokaryotic and eukaryotic cells [14] [15] [16] .