Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/120909
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Type: Journal article
Title: Degradation mechanism of a Golgi-retained distal renal tubular acidosis mutant of the kidney anion exchanger 1 in renal cells
Author: Chu, C.
King, J.
Berrini, M.
Rumley, A.
Apaja, P.
Lukacs, G.
Alexander, R.
Cordat, E.
Citation: American Journal of Physiology - Cell Physiology, 2014; 307(3):C296-C307
Publisher: American Physiological Society
Issue Date: 2014
ISSN: 0363-6143
1522-1563
Statement of
Responsibility: 
Carmen Y. Chu, Jennifer King, Mattia Berrini, Alina C. Rumley, Pirjo M. Apaja, Gergely L. Lukacs, R. Todd Alexander and Emmanuelle Cordat
Abstract: 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.
Keywords: Golgi; quality control; kidney; transporters; membrane protein; epithelium; trafficking; lysosome; proteosome; acidosis; bicarbonate; pH
Rights: © 2014 the American Physiological Society
RMID: 0030071705
DOI: 10.1152/ajpcell.00310.2013
Appears in Collections:Molecular and Biomedical Science publications

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