title: The carboxyl-terminally truncated kidney anion exchanger 1 R901X dRTA mutant is unstable at the plasma membrane.
abstract: Mutations in the SLC4A1 gene coding for kidney anion exchanger 1 (kAE1) cause distal renal tubular acidosis (dRTA). We investigated the fate of the most common truncated dominant dRTA mutant kAE1 R901X. In renal epithelial cells, we found that kAE1 R901X is less abundant than kAE1 wild-type (WT) at the plasma membrane. Although kAE1 WT and kAE1 R901X have similar half-lives, the decreased abundance of kAE1 R901X at the surface is due to an increased endocytosis rate and a decreased recycling rate of endocytosed proteins. We propose that, in polarized renal epithelial cells, the apically mistargeted kAE1 R901X mutant is endocytosed faster than kAE1 WT and its recycling to the basolateral membrane is delayed. This resets the equilibrium, such that kAE1 R901X resides predominantly in an endomembrane compartment, thereby likely participating in development of dRTA disease.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; and Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ensaf
authors.initials: E
authors.lastname: Almomani
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Rawad
authors.initials: R
authors.lastname: Lashhab
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; and Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Alexander
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; and Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada cordat@ualberta.ca.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cordat
mesh_terms: D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte
keywords: acidosis; distal renal tubular acidosis; endocytosis; epithelium; kidney; membrane protein; recycling; trafficking; transporters