Ca2+-driven PDIA6 biomolecular condensation ensures proinsulin folding

The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca2+ storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca2+ triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin. Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of proinsulin.

• Publication year

  2025

• Venue

  Nature Cell Biology

• Publication date

  2025-11-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/s41556-025-01794-8PMID 41219432PMCID 12611771
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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