Figure 2.

Model of Py and CT transport across the ER membrane. (A) On reaching the ER, PDI family members (i.e., PDI, ERp72, and ERp57) disrupt disulfide bonds on Py’s surface (step 1a). ERp29 then extrudes the VP1 carboxy-terminal arm to expose VP2 and VP3 (step 1b), generating a hydrophobic virus. This particle is likely maintained in a soluble state by the BiP-ERdj3 chaperones (step 1c). The hydrophobic virus then integrates into the ER membrane (step 2). ERAD membrane components including Derlin-1, Derlin-2, Sel1L, BAP29/31, and RMA1 are postulated to mediate virus transport across the ER membrane. How Py is released into the cytosol is not well-understood (step 3), but may rely on the ER membrane J proteins (i.e., DNAJ B12, B14, and C18) stimulating binding between the virus and cytosolic Hsp70; reiterative cycles of this binding “pull” the virus into the cytosol. (B) CT arrives to the ER by binding to the host ganglioside GM1 receptor. In the ER, CT is transferred to the Derlin-1-Hrd1 membrane proteins (step 1) potentially mediated by BiP-J protein chaperones. An unidentified reductase reduces CTA to generate the CTA1 peptide (step 2). Next, PDI (bound to Derlin-1 and Hrd1), in its reduced state, unfolds CTA1 (step 3); ensuing PDI oxidation by Ero1 releases the unfolded toxin from PDI. The unfolded toxin presumably crosses the Hrd1 complex to reach the cytosol (step 4). Finally, an unidentified cytosolic factor extracts the toxin into the cytosol to complete the transport event (step 5).