Biogenesis and intracellular trafficking pathway of wild-type (a) and ΔF508 (b) CFTR. The width of the gray arrows is proportional to the relative flux through a particular branch of the pathway. Synthesis and cotranslational integration (step 1) in the ER membrane are followed by folding to a native conformation (step 2). About 25% of wild-type and more than 99% of ΔF508 CFTR molecules are degraded by a process that is mediated by cytoplasmic proteasomes (step 3). Native CFTR molecules (light blue cylinder) are delivered via the Golgi apparatus (not shown) to the plasma membrane (step 4), where they are subject to rapid endocytosis (step 5) to subapical vesicles (light blue lumen). CFTR is recycled to the plasma membrane (step 6), where it can be activated by cAMP-dependent kinases (step 7). Differences in the relative rates of recycling and degradation in lysosomes (pink lumen; step 8) are likely to account for the substantial differences in half-lives between wild-type and ΔF508 CFTR.