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  • XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell

This content will become publicly available on September 24, 2026

Title: XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell
Xanthine dehydrogenase (XDH) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in XDH develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently, there are no therapies for treating human XDH deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematodeCaenorhabditis elegansto model human XDH deficiency using two clinically relevant paradigms: Moco deficiency or loss-of-function mutations inxdh-1,theC. elegansortholog of XDH.Both Moco deficiency andxdh-1loss of function caused the formation of autofluorescent xanthine stones inC. elegans. Surprisingly, only 2% ofxdh-1null mutantC. elegansdeveloped a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation inxdh-1null mutantC. elegans. We isolated multiple loss-of-function mutations in the genesulp-4which encodes a sulfate permease homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly,sulp-4mutant phenotypes were suppressed by mutations in genes that encode for cystathionase (cth-2)or cysteine dioxygenase (cdo-1), members of the sulfur amino acid catabolism pathway required for production of sulfate, a substrate of SULP-4. We propose that sulfate accumulation caused bysulp-4loss of function promotes xanthine stone accumulation. We speculate that sulfate accumulation causes osmotic imbalance, creating conditions in the intestinal lumen that favor xanthine stone accumulation. Supporting this model, a mutation inosm-8that constitutively activates the osmotic stress response also promoted xanthine stone accumulation in anxdh-1mutant background. Thus, our work establishes aC. elegansmodel for human XDH deficiency and identifies the sulfate permeasesulp-4as a critical player controlling xanthine stone accumulation.  more » « less
Award ID(s):
1756912
PAR ID:
10645945
Author(s) / Creator(s):
; ; ; ; ; ; ; ;
Editor(s):
Alkema, Mark J
Publisher / Repository:
PLOS
Date Published:
Journal Name:
PLOS Biology
Volume:
23
Issue:
9
ISSN:
1545-7885
Page Range / eLocation ID:
e3003410
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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