Lysosome-related organelles employ divergent mechanisms to modulate cytosolic zinc homeostasis

Chaoyi Xie, Yi Luo, Yawen Zheng, Bowen Liu, Shibo Song, Jie Wei, Anbing Shi and Yanling Yan

PLOS Genetics, 2026, vol. 22, issue 6, 1-26

Abstract: Elevated environmental zinc levels pose significant toxicity to biological systems, necessitating adaptive responses to mitigate excessive zinc exposure. In C. elegans, a specific lysosome-related organelle, the gut granule, may increase in number and volume with high dietary zinc, thereby lowering cytosolic zinc concentration, though the mechanisms remain unclear. Our results suggest that GLO-1 predominantly controls granule biogenesis, whereas zinc-induced granule expansion involves distinct mechanisms. Further study revealed that high zinc upregulated GLO-1 activity through its GEF complex GLO-3-CCZ-1, by enhancing transcription of GLO-3 and post-translational modification of CCZ-1. Zinc transporter CDF-2 has been identified to mediate zinc influx into gut granules. In this study, analysis of 14 C. elegans CDFs reveals that ZK185.5 (CDF-3) and F19C6.5 (CDF-4) also localize in gut granules. Functional studies suggest that CDF-3, not CDF-4, complements CDF-2 in facilitating zinc influx into gut granules. Unlike CDF-2, the expression of CDF-3 is downregulated in a high zinc diet. These results suggest a modulation in the composition of CDFs within gut granules in response to environmental zinc. Together, our study reveals a sophisticated zinc detoxification mechanism of C. elegans gut granule to uphold cytosolic zinc homeostasis amidst fluctuating environments.Author summary: Maintaining zinc homeostasis is critical for the survival of free-living C. elegans, in which the lysosome-related organelle, the gut granule, plays a pivotal role. In this work, a divergent mechanism adopted by gut granules to protect the animal from high zinc toxicity is revealed. First, zinc stimulates GLO-1 activity through regulation of its GEF complex, which may contribute to gut granule biogenesis. Second, a new zinc transporter, CDF-3, was found to localize to gut granules and mediate zinc influx as CDF-2. Strikingly, unlike CDF-2, the expression of CDF-3 was downregulated upon high zinc treatment, indicating that gut granules rearrange their CDF composition to adapt to a high zinc diet. This study provides new insights into the zinc homeostasis mechanism in the nematode C. elegans.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1012199

DOI: 10.1371/journal.pgen.1012199

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