Revealing the mechanism behind quality control of insulin in the endoplasmic reticulum

Calcium (Ca²⁺) drives many cellular functions, though the way it controls quality of proteins in the endoplasmic reticulum (ER), a cellular organelle that synthesizes and transports proteins, is widely unknown. This control system of protein quality, known as proteostasis, was put under a microscope by researchers to find a more thorough understanding of the process, potentially revealing clues about how to prevent Type 2 diabetes, Alzheimer's and amyotrophic lateral sclerosis (ALS).

The team consisted of researchers across multiple disciplines, lead by Distinguished Associate Professor Masaki Okumura of the Tohoku University Frontier Research Institute for Interdisciplinary Sciences (FRIS) and Graduate School of Life Sciences, in an international collaborative study involving 17 research teams from Japan, Korea, and the UK. Results were published in Nature Cell Biology on November 11, 2025.

With the goal of elucidating Ca²⁺ driven proteostasis in the ER in mind, they found that Ca²⁺ can induce a phase separation in PDIA6, a gene that codes for 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 - such as diabetes.

However, not all is lost if there are mistakes in protein folding. They found that a process called calcium-driven phase separation in the ER essentially creates liquid-like droplets through condensation that can make corrections to proinsulin. Proinsulin is the insulin precursor, and too much of it can indicate a risk for Type 2 diabetes.

"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," said Okumura.

This knowledge meaningfully contributes to our understanding of other calcium-driven processes within cells. In addition, this research could potentially be used in drug development for difficult-to-cure diseases like ALS, Alzheimer's and Type 2 diabetes.