Transcytosis maintains CFTR apical polarity in the face of constitutive and mutation-induced basolateral missorting

Bidaud-Meynard, Aurélien; Bossard, Florian; Schnúr, Andrea; Fukuda, Ryosuke; Veit, Guido; Xu, Haijin; Lukacs, Gergely L.

doi:10.1242/jcs.226886

Cited by 8 publications

(6 citation statements)

References 79 publications

(116 reference statements)

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“…To explore the relative localization of CFTR with apical and basolateral markers, we conducted a triple stain of CFTR with wheat germ agglutinin (WGA), another apical marker (55), and the Na ϩ /K ϩ -ATPase ( Fig. 4).…”

Section: Vx-809 Rearranges Cftr Nhe3 and Enac In Adpkd Cysts Relatimentioning

confidence: 99%

“…Bidaud-Meynard et al (55) have demonstrated that in airway cells basolateral CFTR delivery occurs via both biosynthetic (ϳ35%) and endocytic (ϳ65%) pathways and that basolateral channels are retrieved via basolateral-to-apical transcytosis, enhancing CFTR apical expression by 2-fold and suppressing its degradation. Given that CFTR has been observed in the basolateral membranes of both secretory and absorptive epithelia, the observation that VX-809 increases the localization of CFTR at the basolateral membrane indicates that VX-809 increases the stability of WT CFTR at the basolateral membrane.…”

Section: Vx-809 Rearranges Cftr Nhe3 and Enac In Adpkd Cystsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease

Yanda

Cha

Cebotaru

et al. 2019

Journal of Biological Chemistry

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Edited by Phyllis I. Hanson Autosomal-dominant polycystic kidney disease (ADPKD) induces a secretory phenotype, resulting in multiple fluid-filled cysts. We have previously demonstrated that VX-809, a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR), reduces cyst growth. Here, we show that in normal mice CFTR is located within the cells and also at the apical and basolateral membranes. However, in polycystic kidney disease (pkd1)-knockout mice, CFTR was located at the plasma membrane, consistent with its role in cAMP-dependent fluid secretion. In cystic mice, VX-809 treatment increased CFTR levels at the apical membrane and reduced its association with the endoplasmic reticulum. Surprisingly, VX-809 treatment significantly increased CFTR's co-localization with the basolateral membrane in cystic mice. Na ؉ /H ؉ exchanger 3 (NHE3) is present in pkd1-knockout and normal mice and in proximal tubule-derived, cultured pkd1-knockout cells. VX-809 increased the expression, activity, and apical plasma membrane localization of NHE3. Co-localization of epithelial sodium channel (ENaC) with the plasma membrane was reduced in cysts in pkd1-knockout mice, consistent with an inability of the cysts to absorb fluid. Interestingly, in the cystic mice, VX-809 treatment increased ENaC levels at the apical plasma membrane consistent with fluid absorption. Thus, VX-809 treatment of pkd1-null mouse kidneys significantly affected CFTR, NHE3, and ENaC, altering the cyst phenotype from one poised toward fluid secretion toward one more favorable for absorption. VX-809 also altered the location of CFTR but not of NHE3 or ENaC in normal mice. Given that VX-809 administration is safe, it may have potential utility for treating patients with ADPKD.

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Section: Vx-809 Rearranges Cftr Nhe3 and Enac In Adpkd Cysts Relatimentioning

confidence: 99%

Section: Vx-809 Rearranges Cftr Nhe3 and Enac In Adpkd Cystsmentioning

confidence: 99%

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease

Yanda

Cha

Cebotaru

et al. 2019

Journal of Biological Chemistry

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“…The transition of CD13 from the adhesion to apical site is reminiscent of basolateral-to-apical transcytosis described for a few proteins 53,54 . CFTR was shown to undergo apical-transcytosis through a Rab11-independent mechanism involving EEA1 + vesicles, raising the possibility that CD13 may redistribute to the AMIS through a transcytosis-like pathway.…”

Section: Discussionmentioning

confidence: 86%

CD13 orients the apical-basal polarity axis necessary for lumen formation

et al. 2021

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Polarized epithelial cells can organize into complex structures with a characteristic central lumen. Lumen formation requires that cells coordinately orient their polarity axis so that the basolateral domain is on the outside and apical domain inside epithelial structures. Here we show that the transmembrane aminopeptidase, CD13, is a key determinant of epithelial polarity orientation. CD13 localizes to the apical membrane and associates with an apical complex with Par6. CD13-deficient cells display inverted polarity in which apical proteins are retained on the outer cell periphery and fail to accumulate at an intercellular apical initiation site. Here we show that CD13 is required to couple apical protein cargo to Rab11-endosomes and for capture of endosomes at the apical initiation site. This role in polarity utilizes the short intracellular domain but is independent of CD13 peptidase activity.

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“…It is known that in secretory epithelia, newly processed CFTR first traffics to the basolateral membrane and then is transcytosed to the apical membrane. 61 Thus, it is not unusual to detect CFTR colocalization within the basolateral membrane. One can readily see that in del4 cholangiocytes, the colocalization of CFTR with the basolateral marker is reduced, likely contributing to cyst formation in a manner similar to that in ADPKD.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease

Yanda

Tomar

Cebotaru

2021

Cellular and Molecular Gastroenterology and Hepatology

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Autosomal recessive polycystic kidney disease (ARPKD) causes severe disease in babies in the womb. Those who survive the neonatal period face chronic kidney and liver disease throughout their life. The overall goal of our study was to uncover therapeutic strategies to treat ARPKD. BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD)Q5 is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. METHODS:We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using Western blotting and protein trafficking using confocal microscopy. RESULTS:We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPCmutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values.CONCLUSIONS: FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.

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Transcytosis maintains CFTR apical polarity in the face of constitutive and mutation-induced basolateral missorting

Cited by 8 publications

References 79 publications

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease

CD13 orients the apical-basal polarity axis necessary for lumen formation

Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease

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