Calcium (Ca2+) drives many cellular functions, although how it controls the quality of proteins in the endoplasmic reticulum (ER), a cellular organelle that synthesizes and transports proteins, is largely unknown. This protein quality control system, known as proteostasis, has been put under the microscope by researchers to gain a deeper understanding of the process, potentially revealing clues about how to prevent type 2 diabetes, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).
The team consisted of researchers across multiple disciplines, led by Distinguished Associate Professor Masaki Okumura of the Tohoku University Frontier Research Institute for Interdisciplinary Sciences (FRIS) and the Graduate School of Life Sciences, in an international collaborative study involving 17 research groups from Japan, Korea and the United Kingdom. The results were published in Nature Cell Biology on November 11, 2025.
With the aim of clarifying Ca2+ driven proteostasis in the ER in the brain, they found that Ca2+ can induce phase separation in PDIA6, a gene encoding a specific, ER-localized protein responsible for protein folding and function. Therefore, if this protein loses its function, misfolding can occur. The consequences for improperly folded proteins can be dire – like diabetes.
However, all is not lost if there are errors in protein folding. They found that a process called calcium phase separation in the ER essentially creates liquid-like droplets through condensation that can make corrections to proinsulin. Proinsulin is the precursor to insulin, and too much can indicate a risk for type 2 diabetes.
“To keep them working smoothly, we need these condensation-like droplets to ensure that proinsulin is folded correctly – as opposed to forming large, aggregated clumps that can disrupt normal pathways and cause negative health outcomes.”
Masaki Okumura, Distinguished Associate Professor, Tohoku University
This knowledge contributes substantially to our understanding of other calcium-driven processes within cells. In addition, this research could potentially be used in the development of drugs for difficult-to-treat diseases such as ALS, Alzheimer’s and type 2 diabetes.
