Jensen T J, Loo M A, Pind S, Williams D B, Goldberg A L, Riordan J R
S. C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Arizona 85259, USA.
Cell. 1995 Oct 6;83(1):129-35. doi: 10.1016/0092-8674(95)90241-4.
The molecular components of the quality control system that rapidly degrades abnormal membrane and secretory proteins have not been identified. The cystic fibrosis transmembrane conductance regulator (CFTR) is an integral membrane protein to which this quality control is stringently applied; approximately 75% of the wild-type precursor and 100% of the delta F508 CFTR variant found in most CF patients are rapidly degraded before exiting from the ER. We now show that this ER degradation is sensitive to inhibitors of the cytosolic proteasome, including lactacystin and certain peptide aldehydes. One of the latter compounds, MG-132, also completely blocks the ATP-dependent conversion of the wild-type precursor to the native folded form that enables escape from degradation. Hence, CFTR and presumably other intrinsic membrane proteins are substrates for proteasomal degradation during their maturation within the ER.
能够快速降解异常膜蛋白和分泌蛋白的质量控制系统的分子成分尚未明确。囊性纤维化跨膜传导调节因子（CFTR）是一种整合膜蛋白，该质量控制系统严格作用于它；在大多数囊性纤维化患者中发现的约75%的野生型前体和100%的ΔF508 CFTR变体在从内质网中排出之前就被迅速降解。我们现在表明，这种内质网降解对胞质蛋白酶体的抑制剂敏感，包括乳胞素和某些肽醛。后一种化合物之一MG-132也完全阻断了野生型前体向能够逃避降解的天然折叠形式的ATP依赖性转化。因此，CFTR以及可能的其他内在膜蛋白在其在内质网中的成熟过程中是蛋白酶体降解的底物。
