Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B

Bergeron, Marc J; Bürzle, Marc; Kovacs, Gergely; Simonin, Alexandre; Hediger, Matthias A (2011). Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B. Journal of biological chemistry, 286(13), pp. 11242-53. Bethesda, Md.: American Society for Biochemistry and Molecular Biology 10.1074/jbc.M110.171728

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Renal excretion of citrate, an inhibitor of calcium stone formation, is controlled mainly by reabsorption via the apical Na(+)-dicarboxylate cotransporter NaDC1 (SLC13A2) in the proximal tubule. Recently, it has been shown that the protein phosphatase calcineurin inhibitors cyclosporin A (CsA) and FK-506 induce hypocitraturia, a risk factor for nephrolithiasis in kidney transplant patients, but apparently through urine acidification. This suggests that these agents up-regulate NaDC1 activity. Using the Xenopus lævis oocyte and HEK293 cell expression systems, we examined first the effect of both anti-calcineurins on NaDC1 activity and expression. While FK-506 had no effect, CsA reduced NaDC1-mediated citrate transport by lowering heterologous carrier expression (as well as endogenous carrier expression in HEK293 cells), indicating that calcineurin is not involved. Given that CsA also binds specifically to cyclophilins, we determined next whether such proteins could account for the observed changes by examining the effect of selected cyclophilin wild types and mutants on NaDC1 activity and cyclophilin-specific siRNA. Interestingly, our data show that the cyclophilin isoform B is likely responsible for down-regulation of carrier expression by CsA and that it does so via its chaperone activity on NaDC1 (by direct interaction) rather than its rotamase activity. We have thus identified for the first time a regulatory partner for NaDC1, and have gained novel mechanistic insight into the effect of CsA on renal citrate transport and kidney stone disease, as well as into the regulation of membrane transporters in general.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Bürzle, Marc; Kovacs, Gergely; Simonin, Alexandre and Hediger, Matthias

ISSN:

0021-9258

Publisher:

American Society for Biochemistry and Molecular Biology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:23

Last Modified:

06 Dec 2013 13:29

Publisher DOI:

10.1074/jbc.M110.171728

PubMed ID:

21257749

Web of Science ID:

000288797100036

URI:

https://boris.unibe.ch/id/eprint/8166 (FactScience: 213659)

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