The UPS complexes located in the ER membrane (Derlin-1, RMA1, Ubc6e and p97) and cytoplasm (Hsp70 and CHIP) are shown. The figure demonstrates the polyubiquitylation of CFTR due to membrane-bound and cytosolic E3 ubiquitin ligase complexes. While the ubiquitylation likely occurs on the cytoplasmic domains of CFTR, the exact lysine residues conjugated with ubiquitin are unknown. p97 and possibly other associated factors are thought to participate in the extraction and delivery of CFTR from the ER membrane to the cytosolic proteasome. However, it is unknown whether the CFTR protein is extracted from the membrane in one piece, or degraded into smaller domains before retrotranslocation. Membrane spanning domains are depicted in sepia and the cytosolic domains in aqua.