Crossing the endoplasmic reticulum (ER) membrane is an irreversible process for most proteins. In some cases, however, this flow is reversed and misfolded proteins retained in the ER are retrotranslocated to the cytosol via ERAD to be degraded by the proteasome. This pathway is also exploited by small pathogens, especially non-enveloped viruses and some bacterial toxins, to gain access to the cytosol. In these cases, antigenic particles that reach the ER by different means suffer molecular redox rearrangements and binding to PDI allowing them to be transported back to the cytosol or nucleus. Well-known examples are infections mediated by Polyomaviruses (Py) and Simian virus 40 (SV40) extensively studied in the field of carcinogenesis. After SV40 interaction with the GM1 receptor on the cell surface, the particle enters the host cell through endocytosis and traffics via the caveosome (a particular caveolin containing endosome with neutral pH) towards the ER compartment [75, 76] . SV40-coated pentamers are linked to each other by disulfide bonds between cysteine 104 (C104). Further isomerisation in the ER is crucial for the viral uncoating process. In vitro cell screening shows that among all ER-resident proteins, PDI and ERp57 more specifically regulate SV40 infection [75] . PDI silencing substantially decreases SV40 infection that is also dependent on some redox sensitive cysteines on the viral particle [75] . PDI cooperation with ERassociated ERAD proteins Derlin-1 and Sel1L is Ca dependent and facilitates SV40 traffic through ERAD [75] . A similar pathway is used by some nonobligatory intracellular bacteria that exert their effect through production of potent endotoxins, such as diphtheria toxin (DT) and cholera toxin (CT). These proteins function similarly to some plant toxins, such as ricin and abrin. Conversion into toxic proteins involves cleavage of their interchain disulfide bond, allowing them to traffic into the endocytic pathway within the host cell [77, 78] . In humans, CT is derived from the Bacterium Vibrio cholerae that causes cholera disease and has 2 subunits (A1 and A2). The protein first attaches to the host cell surface via GM1 and the subunit A2, which contains a KDEL sequence, and is transported back to the ER (see earlier discussion). There, PDI reduces and unfolds A2 and A1 that exit the ER via the Sec61 channel into the cytosol. PDI in the reduced state (reaction 1, Figure 1 ) binds to the toxin and subsequent oxidation of PDI, probably via Ero1α, enables the release of CT toxin [79, 80] . The active polypeptide A1 efficiently modifies a heterotrimeric G protein in the cytosol that leads to massive loss of chlorine and water secretion by intestinal epithelial cells in mammals, resulting in severe diarrhoea.