Unraveling trafficking of the kidney anion exchanger 1 in polarized MDCK epithelial cellsThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 949-959 ◽  
Author(s):  
Emmanuelle Cordat
Keyword(s):  
Anion Exchanger ◽  
Basolateral Membrane ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Anion Exchanger 1 ◽  
Collecting Tubule ◽  
Health And Disease ◽  
Renal Tubular ◽  
Shed Light ◽  
Selection Of

Kidney anion exchanger 1 (kAE1) is a membrane glycoprotein expressed at the basolateral membrane of type A intercalated cells in the kidney collecting tubule. Mutations occurring in the gene encoding this protein can give rise to distal renal tubular acidosis (dRTA), a disease characterized by an impaired urine acidification, nephrocalcinosis, and renal failure. Here we review how the study of dRTA mutants in polarized epithelial cells has shed light on the cellular mechanisms resulting in this renal disease.

scholarly journals The carboxyl-terminally truncated kidney anion exchanger 1 R901X dRTA mutant is unstable at the plasma membrane

2016 ◽  
Vol 310 (9) ◽  
pp. C764-C772 ◽  
Author(s):  
Ensaf Almomani ◽  
Rawad Lashhab ◽  
R. Todd Alexander ◽  
Emmanuelle Cordat
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Anion Exchanger ◽  
Basolateral Membrane ◽  
Recycling Rate ◽  
Wild Type ◽  
Anion Exchanger 1 ◽  
Renal Epithelial Cells ◽  
Gene Coding ◽  
Renal Tubular

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.

Topology models of anion exchanger 1 that incorporate the anti-parallel V-shaped motifs found in the EM structureThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 148-156 ◽  
Author(s):  
Teruhisa Hirai ◽  
Naotaka Hamasaki ◽  
Tomohiro Yamaguchi ◽  
Yohei Ikeda
Keyword(s):  
Anion Exchanger ◽  
Peer Review Process ◽  
Three Dimensional ◽  
Structural Similarity ◽  
Dimensional Structure ◽  
Membrane Bilayer ◽  
Anion Exchanger 1 ◽  
Advantages And Disadvantages ◽  
Health And Disease ◽  
Selection Of

We recently published the three-dimensional structure of the membrane domain of human erythrocyte anion exchanger 1 (AE1) at 7.5 Å resolution, solved by electron crystallography. The structure exhibited distinctive anti-parallel V-shaped motifs, which protrude from the membrane bilayer on both sides. Similar motifs exist in the previously reported structure of a bacterial chloride channel (ClC)-type protein. Here, we propose two topology models of AE1 that reflect the anti-parallel V-shaped structural motifs. One is assumed to have structural similarity with the ClC protein and the other is only assumed to have internal repeats, as is often the case with transporters. Both models are consistent with most topological results reported thus far for AE1, each having advantages and disadvantages.

Degradation mechanism of a Golgi-retained distal renal tubular acidosis mutant of the kidney anion exchanger 1 in renal cells

2014 ◽  
Vol 307 (3) ◽  
pp. C296-C307 ◽  
Author(s):  
Carmen Y. Chu ◽  
Jennifer King ◽  
Mattia Berrini ◽  
Alina C. Rumley ◽  
Pirjo M. Apaja ◽  
...  
Keyword(s):  
Quality Control ◽  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Mammalian Cells ◽  
Degradation Mechanism ◽  
Basolateral Membrane ◽  
Distal Renal Tubular Acidosis ◽  
Anion Exchanger 1 ◽  
Chemical Chaperone ◽  
Renal Tubular

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.

Defective kidney anion-exchanger 1 (AE1, Band 3) trafficking in dominant distal renal tubular acidosis (dRTA).

2005 ◽  
Vol 72 ◽  
pp. 47-63 ◽  
Author(s):  
Ashley M. Toye
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Apical Membrane ◽  
Basolateral Membrane ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Anion Exchanger 1 ◽  
C Terminus ◽  
N Terminus ◽  
Renal Tubular

dRTA (distal renal tubular acidosis) results from the failure of the a-intercalated cells in the distal tubule of the nephron to acidify the urine. A truncated form of AE1 (anion-exchanger 1; Band 3), kAE1 (kidney isoform of AE1), is located in the basolateral membrane of the intercalated cell. Mutations in the AE1 gene cause autosomal dominant and recessive forms of dRTA. All the dominant dRTA mutations investigated cause aberrant trafficking of kAE1, resulting in its intracellular retention or mistargeting to the apical plasma membrane. Therefore the intracellular retention of hetero-oligomers containing wild-type and dRTA mutants, or the mistargeted protein in the apical membrane neutralizing acid secretion, explains dominant dRTA. The kAE1 (Arg901→stop) mutant has been studied in more detail, since the mistargeting kAE1 (Arg901→stop) from the basolateral to the apical membrane is consistent with the removal of a basolateral localization signal. The C-terminal amino acids deleted by the Arg901→stop mutation, contain a tyrosine motif and a type II PDZ interaction domain. The tyrosine residue (Tyr904), but not the PDZ domain, is critical for basolateral localization. In the absence of the N-terminus of kAE1, the C-terminus was not sufficient to localize kAE1 to the basolateral membrane. This suggests that a determinant within the kAE1 N-terminus co-operates with the C-terminus for kAE1 basolateral localization. Interestingly, Tyr359, in the N-terminal domain, and Tyr904 in the C-terminus of AE1 are phosphorylated in red blood cells. A potential scheme is suggested where successive phosphorylation of these residues is necessary for correct localization and recycling of kAE1 to the basolateral membrane.

Band 3 Edmonton I, a novel mutant of the anion exchanger 1 causing spherocytosis and distal renal tubular acidosis

2010 ◽  
Vol 426 (3) ◽  
pp. 379-388 ◽  
Author(s):  
Carmen Chu ◽  
Naomi Woods ◽  
Nunghathai Sawasdee ◽  
Helene Guizouarn ◽  
Bernard Pellissier ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Failure To Thrive ◽  
Renal Stones ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Kidney Cells ◽  
Gene Encoding ◽  
Anion Exchanger 1 ◽  
Renal Tubular

dRTA (distal renal tubular acidosis) and HS (hereditary spherocytosis) are two diseases that can be caused by mutations in the gene encoding the AE1 (anion exchanger 1; Band 3). dRTA is characterized by defective urinary acidification, leading to metabolic acidosis, renal stones and failure to thrive. HS results in anaemia, which may require regular blood transfusions and splenectomy. Mutations in the gene encoding AE1 rarely cause both HS and dRTA. In the present paper, we describe a novel AE1 mutation, Band 3 Edmonton I, which causes dominant HS and recessive dRTA. The patient is a compound heterozygote with the new mutation C479W and the previously described mutation G701D. Red blood cells from the patient presented a reduced amount of AE1. Expression in a kidney cell line showed that kAE1 (kidney AE1) C479W is retained intracellularly. As kAE1 is a dimer, we performed co-expression studies and found that, in kidney cells, kAE1 C479W and G701D proteins traffic independently from each other despite their ability to form heterodimers. Therefore the patient carries one kAE1 mutant that is retained in the Golgi (G701D) and another kAE1 mutant (C479W) located in the endoplasmic reticulum of kidney cells, and is thus probably unable to reabsorb bicarbonate into the blood. We conclude that the C479W mutant is a novel trafficking mutant of AE1, which causes HS due to a decreased cell-surface AE1 protein and results in dRTA due to its intracellular retention in kidney.

A Novel Mutation in the Anion Exchanger 1 Gene Is Associated With Familial Distal Renal Tubular Acidosis and Nephrocalcinosis

PEDIATRICS ◽  
2003 ◽  
Vol 112 (6) ◽  
pp. 1361-1367 ◽  
Author(s):  
L. Cheidde ◽  
T. C. Vieira ◽  
P. R. M. Lima ◽  
S. T. O. Saad ◽  
I. P. Heilberg
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Novel Mutation ◽  
Distal Renal Tubular Acidosis ◽  
Anion Exchanger 1 ◽  
Renal Tubular

Dominant and Recessive Distal Renal Tubular Acidosis Mutations of Kidney Anion Exchanger 1 Induce Distinct Trafficking Defects in MDCK Cells

Traffic ◽  
2005 ◽  
Vol 7 (2) ◽  
pp. 117-128 ◽  
Author(s):  
Emmanuelle Cordat ◽  
Saranya Kittanakom ◽  
Pa-thai Yenchitsomanus ◽  
Jing Li ◽  
Kai Du ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Mdck Cells ◽  
Distal Renal Tubular Acidosis ◽  
Anion Exchanger 1 ◽  
Trafficking Defects ◽  
Renal Tubular

Trafficking defect of mutant kidney anion exchanger 1 (kAE1) proteins associated with distal renal tubular acidosis and Southeast Asian ovalocytosis

2006 ◽  
Vol 350 (3) ◽  
pp. 723-730 ◽  
Author(s):  
Nunghathai Sawasdee ◽  
Wandee Udomchaiprasertkul ◽  
Sansanee Noisakran ◽  
Nanyawan Rungroj ◽  
Varaporn Akkarapatumwong ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Southeast Asian ◽  
Distal Renal Tubular Acidosis ◽  
Anion Exchanger 1 ◽  
Renal Tubular

scholarly journals Anion exchanger 1 mutations associated with distal renal tubular acidosis in the Thai population

2003 ◽  
Vol 48 (9) ◽  
pp. 451-456 ◽  
Author(s):  
Pa-thai Yenchitsomanus ◽  
Nunghathai Sawasdee ◽  
Atchara Paemanee ◽  
Thitima Keskanokwong ◽  
Somkiat Vasuvattakul ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Distal Renal Tubular Acidosis ◽  
Thai Population ◽  
Anion Exchanger 1 ◽  
Renal Tubular
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