Degradation mechanism of a Golgi-retained distal renal tubular acidosis mutant of the kidney anion exchanger 1 in renal cells
| Autor: | Gergely L. Lukacs, Alina C. Rumley, Jennifer C. King, Pirjo M. Apaja, Carmen Y. S. Chu, Mattia Berrini, Emmanuelle Cordat, R. Todd Alexander |
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| Rok vydání: | 2014 |
| Předmět: |
Physiology
Mutant Golgi Apparatus Biology Endoplasmic Reticulum Kidney Cell Line Madin Darby Canine Kidney Cells symbols.namesake Dogs Distal renal tubular acidosis Anion Exchange Protein 1 Erythrocyte Lysosome medicine Animals Humans Cycloheximide Epithelial polarity Protein Synthesis Inhibitors Endosomal Sorting Complexes Required for Transport Cell Membrane Ubiquitination Acidosis Renal Tubular Cell Biology Golgi apparatus medicine.disease Endocytosis Cell biology Protein Transport HEK293 Cells medicine.anatomical_structure Biochemistry Membrane protein Gene Knockdown Techniques Mutation Proteolysis symbols Chemical chaperone Lysosomes HeLa Cells |
| Zdroj: | American Journal of Physiology-Cell Physiology. 307:C296-C307 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00310.2013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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