The latter applies a fortiori when considering membrane proteins such as Class I MHC products, one of the few examples for which there is evidence of a soluble cytoplasmic intermediate with its TM segment present and intact. We show here that the cytoplasmic chaperone BAT3 is recruited to Derlin2 at the ER membrane, can engage ER glycoproteins that are subject to dislocation, and that BAT3 is required for dislocation of TCRa. A disruption of proteasomal degradation not only halts breakdown of ER-derived proteins, but often leads to their accumulation within the ER lumen. This is complemented by the requirement for Timosaponin-BII poly-ubiquitylation to complete the dislocation reaction, giving rise to the idea that dislocation of a substrate is mostly tightly coupled to its degradation. Examples exist where such coupling is undone, for instance the Human Cytomegalovirus proteins US11 and US2, both of which funnel Class I MHC heavy chains into a dislocation pathway, and result in accumulation of the heavy chain in the Tenacissoside-X cytoplasm when proteasomal proteolysis is blocked. We showed that in the presence of the EBV-DUB, ERderived glycoproteins accumulate in the cytoplasm but are not degraded. Even though these ER proteins accumulate in the cytoplasm, it is unclear how they are maintained in a soluble state once there. The cytoplasm contains folding machinery that prevents protein aggregation. HSC70 and HSP90, and their heat-shock induced counterparts, are examples of chaperones that engage unfolded polypeptides in the cytoplasm. Even though these chaperones have been linked to ER protein maturation and dislocation, particularly for the example of HSC70 and its involvement in dislocation of the misfolded cystic fibrosis transmembrane conductance regulator DF508, it remains to be established whether they play a direct role in dislocation and bridge the gap between the chaperone-rich ER lumen and the proteasome. BAT3 has a role in the degradation of defective polypeptides synthesized at the ribosome, and may shuttle such substrates to the proteasome.