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Degradation mechanism of a Golgi-retained distal tubular acidosis mutant of the kidney Anion Exchanger 1 in renal cells Open Access


Other title
kidney anion exchanger 1
peripheral quality-control machinery
Golgi-retained dRTA mutant
Distal renal tubular acidosis
Type of item
Degree grantor
University of Alberta
Author or creator
Berrini, Mattia
Supervisor and department
Cordat, Emmanuelle
Examining committee member and department
Leslie, Elaine
Young, James
Cordat, Emmanuelle
Casey, Joe
Department of Physiology
Cell Biology
Date accepted
Graduation date
Master of Science
Degree level
Distal renal tubular acidosis (dRTA) is a renal disease caused in some cases by mutations in the SLC4A1 gene encoding the kidney anion exchanger 1 (kAE1). Both recessive and dominant mutations result in mis-trafficking of proteins, preventing them from reaching the basolateral membrane of renal epithelial cells where their function is needed. kAE1 G701D is a functional, Golgi-retained dRTA mutant. The purpose of this thesis is to understand the degradation pathways of kAE1 G701D. We show that this mutant is poly-ubiquitylated and degraded by both lysosomal and proteasomal pathways. We provide evidence that the Nedd4 family interacting protein 1 (Ndfip1) interacts with kAE1 G701D, suggesting a possible role of Ndfip1 in the ubiquitylation process of this mutant. Also, we show that this mutant reaches temporarily the cell surface where it is endocytosed and degraded by the lysosomes via a peripheral quality-control machinery dependent mechanism. Furthermore we show that the function of kAE1 G701D is rescued at the cell surface upon inhibition of the lysosome and incubation with the chemical chaperone dimethyl sulfoxide (DMSO). This study suggests that modulating the peripheral quality-control machinery may provide novel therapeutic strategies for the treatment of dRTA patients.
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