Sardana lab preprint: Ers1

05 Mar 2026
by Richa
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Sardana Lab preprint Ers1/Cystinosin

Cystinosin/Ers1 functions in redox homeostasis in the early secretory pathway

Julia Zhu, Sumanth Mosale, Jade Bowerman, Solomon Baik, Katie Munechika, Nathan Wu, Aleksandra Skirycz, Haiyuan Yu, Miguel Piñeros, Richa Sardana Biorxiv, 2026

Check out the new work from our lab on the novel extra-lysosomal role of Ers1/Cystinosin in redox homestasis in the early Golgi led by graduate student, Julia Zhu: available at DOI link

TL;DR :

  • Mutations in Cystinosin (CTNS) cause cystinosis- a rare, monogenic, autosomal recessive disorder. Cystinosin mediates proton-dependent transport of cystine from the lysosome lumen to the cytosol. However, there is increasing evidence that the role of CTNS may extend beyond cystine transport, but these functions are poorly understood. Our work questions several assumptions about cystinosin function.

  • Yeast cystinosin homolog functions at the Golgi, not lysosome. Ers1, the yeast homolog of CTNS, is well conserved with the highest conservation in the functionally important PQ loops. The first surprise was that Ers1 does not localize to the yeast vacuole (lysosome) at all. We found that Ers1 predominantly localizes and functions at the early-Golgi. This localization makes sense given the discovery of Ers1 (ERD suppressor 1), as a multicopy suppressor of loss of Erd1, an early Golgi protein involved in ER and Golgi resident protein maintenance.

  • We also find that Ers1 localization at the Golgi is tightly regulated. Ers1 is recycled back from the medial to early-Golgi by the Vps74-COPI pathway, and any Ers1 that escapes recycling is readily targeted for degradation by the Dsc E3 ubiquitin ligases complex that maintains Golgi protein quality control.

  • Both our metabolomics data and prior studies demonstrate that Ers1 deletion does not result in cystine accumulation in yeast. Given that Ers1 localizes to the early-Golgi at steady state, it is unlikely to transport cystine across the Golgi membrane in vivo since no cystine accumulates in the Golgi. We were also unable to detect cystine-dependent transport by Ers1 in TEVC experiments using Xenopus oocytes.

  • Similar to what has been reported for CTNS, loss of Ers1 is linked to increased oxidative stress. We uncovered a strong genetic interaction with the ER and early Golgi-localized putative glutaredoxins. Glutaredoxins are thought to use glutathione (GSH) as the electron donor to reduce protein oxidation. Cystine transport associated residues were dispensable, but the C-terminal cytosolic tail was required for this interaction. It is likely that a non-transport structural role of Ers1 by recruitment of an interactor in part via its cytosolic C-terminal tail. Interestingly, CTNS-LKG, a splicing isoform of CTNS that has significant extra-lysosomal localization, can functionally replace Ers1.

  • These observations fundamentally challenge current paradigms in our understanding of cystinosin function and perhaps how we think about other PQ-loop family proteins, and opens so many new areas of inquiry- what solute, if any, does Ers1 transport across the Golgi membrane? Are CTNS and CTNS-LKG also capable of transporting solutes other than cystine? What roles does CTNS-LKG play in the extra-lysosomal locations? Can these help us understand cystinosis pathology and/or understand the role of cystinosin function in the context of other cellular pathways such as ferroptosis signaling?