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首页> 外文期刊>Molecular and Cellular Biology >Interference with Ubiquitination in CFTR Modifies Stability of Core Glycosylated and Cell Surface Pools
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Interference with Ubiquitination in CFTR Modifies Stability of Core Glycosylated and Cell Surface Pools

机译：CFTR泛素化干扰修改核心糖基化和细胞表面池的稳定性。

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It is recognized that both wild-type and mutant CFTR proteins undergo ubiquitination at multiple lysines in the proteins and in one or more subcellular locations. We hypothesized that ubiquitin is added to specific sites in wild-type CFTR to stabilize it and at other sites to signal for proteolysis. Mass spectrometric analysis of wild-type CFTR identified ubiquitinated lysines 68, 710, 716, 1041, and 1080. We demonstrate that the ubiquitinated K710, K716, and K1041 residues stabilize wild-type CFTR, protecting it from proteolysis. The polyubiquitin linkage is predominantly K63. N-tail mutants, K14R and K68R, lead to increased mature band C CFTR, which can be augmented by proteasomal (but not lysosomal) inhibition, allowing trafficking to the surface. The amount of CFTR in the K1041R mutant was drastically reduced and consisted of bands A/B, suggesting that the site in transmembrane 10 (TM10) was critical to further processing beyond the proteasome. The K1218R mutant increases total and cell surface CFTR, which is further accumulated by proteasomal and lysosomal inhibition. Thus, ubiquitination at residue 1218 may destabilize wild-type CFTR in both the endoplasmic reticulum (ER) and recycling pools. Small molecules targeting the region of residue 1218 to block ubiquitination or to preserving structure at residues 710 to 716 might be protein sparing for some forms of cystic fibrosis.
机译：公认的是，野生型和突变型CFTR蛋白都在蛋白质中的多个赖氨酸以及一个或多个亚细胞位置处进行泛素化。我们假设泛素被添加到野生型CFTR的特定位点以稳定它，并在其他位点发出信号进行蛋白水解。野生型CFTR的质谱分析确定了泛素化的赖氨酸68、710、716、1041和1080。我们证明了泛素化的K710，K716和K1041残基稳定了野生型CFTR，使其免受蛋白水解。聚泛素键主要是K63。 N-tail突变体K14R和K68R导致成熟条带C CFTR的增加，可以通过蛋白酶体（但不是溶酶体）抑制来增强，从而允许其转运到表面。 K1041R突变体中CFTR的数量大大减少，并由A / B带组成，这表明跨膜10（TM10）中的位点对于进一步加工超出蛋白酶体至关重要。 K1218R突变体增加总细胞表面CFTR，并通过蛋白酶体和溶酶体抑制进一步积累。因此，残基1218处的泛素化作用可能使内质网（ER）和回收池中的野生型CFTR不稳定。针对某些形式的囊性纤维化，靶向残基1218区域以阻断泛素化或在残基710至716保留结构的小分子可能会保留蛋白质。

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