Degradation mechanism of a Golgi-retained distal renal tubular acidosis mutant of the kidney anion exchanger 1 in renal cells
Degradation mechanism of a Golgi-retained distal renal tubular acidosis mutant of the kidney anion exchanger 1 in renal cells
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DOI：
10.1152/ajpcell.00310.2013
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发表时间：
2014-08-01
影响因子：
5.5
通讯作者：
Cordat, Emmanuelle
中科院分区：
文献类型：
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作者：
Chu, Carmen Y.;King, Jennifer;Cordat, Emmanuelle
远端肾小管酸中毒（dRTA）可由编码阴离子交换剂1（AE1）的SLC4A1基因突变引起。隐性和显性突变都会导致蛋白质的误作用，阻止它们到达肾上皮细胞的基底外侧膜，而那里需要它们的功能。在这项研究中，我们发现两个dRTA突变体过早降解。因此，我们研究了保留在高尔基体中的肾AE1 G701D突变体的降解途径。很少有人知道从哺乳动物细胞的高尔基体室的非天然膜蛋白的降解。我们发现肾脏AE1 G701D突变体被多泛素化并被溶酶体和蛋白体降解。这种突变体到达质膜，在那里它通过依赖于外周质量控制机制的机制被溶酶体内吞和降解。此外，我们发现，突变体的功能被救出后，在细胞表面的溶酶体抑制和孵育的化学伴侣。我们的结论是，调节外周质量控制机制可能提供一种新的治疗选择与dRTA患者由于高尔基体保留突变的治疗。
Distal renal tubular acidosis (dRTA) can be caused by mutations in the SLC4A1 gene encoding the anion exchanger 1 (AE1). Both recessive and dominant mutations result in mistrafficking of proteins, preventing them from reaching the basolateral membrane of renal epithelial cells, where their function is needed. In this study, we show that two dRTA mutants are prematurely degraded. Therefore, we investigated the degradation pathway of the kidney AE1 G701D mutant that is retained in the Golgi. Little is known about degradation of nonnative membrane proteins from the Golgi compartments in mammalian cells. We show that the kidney AE1 G701D mutant is polyubiquitylated and degraded by the lysosome and the proteosome. This mutant reaches the plasma membrane, where it is endocytosed and degraded by the lysosome via a mechanism dependent on the peripheral quality control machinery. Furthermore, we show that the function of the mutant is rescued at the cell surface upon inhibition of the lysosome and incubation with a chemical chaperone. We conclude that modulating the peripheral quality control machinery may provide a novel therapeutic option for treatment of patients with dRTA due to a Golgi-retained mutant.