Calcium (Ca²⁺) regulates many cellular functions, but its role in maintaining protein quality in the endoplasmic reticulum (ER)—the organelle responsible for protein synthesis and transport—has remained largely unclear. Researchers have now investigated this system, known as proteostasis, uncovering mechanisms that could shed light on conditions such as Type 2 diabetes, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
The study was led by Japanese scientist Distinguished Associate Professor Masaki Okumura of Tohoku University’s Frontier Research Institute for Interdisciplinary Sciences (FRIS) and Graduate School of Life Sciences, in collaboration with 17 research teams from Japan, Korea, and the UK. The findings were published in Nature Cell Biology on November 11, 2025.
The team discovered that Ca²⁺ can trigger phase separation in PDIA6, a gene encoding an ER-localized protein critical for proper protein folding. Dysfunction in PDIA6 can lead to misfolded proteins, which are associated with diseases like diabetes.
Importantly, the researchers found that calcium-driven phase separation in the ER can form liquid-like condensates that help correct misfolded proinsulin, the precursor to insulin. Since excessive proinsulin levels are linked to an increased risk of Type 2 diabetes, this mechanism may play a vital role in preventing metabolic disorders.
Masaki Okumura said, “To keep everything running smoothly, we need these condensation-like droplets to ensure proinsulin is properly folded—as opposed to forming large, aggregate clumps that can disrupt the normal pathways and cause negative health outcomes.”
This study provides key insights into how calcium signaling maintains ER proteostasis and suggests potential therapeutic targets for diseases caused by protein misfolding.
Source: Tohoku Press
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