Cell stress sensor IRE1 reveals how cells survive damage

That switch is called IRE1. It is a protein embedded in the membrane of the endoplasmic reticulum, the part of the cell where proteins are made and folded. When too many misfolded proteins accumulate, IRE1 activates a broader recovery programme known as the unfolded protein response (UPR).

Exactly how IRE1 detects that something has gone wrong had long remained unclear. The researchers used extensive computer simulations, totalling 137 microseconds of atomistic molecular modelling, to map the molecular movements of IRE1. They identified two binding pockets on the protein where misfolded proteins attach. That binding stabilises larger IRE1 complexes, amplifying the distress signal.

Relevant for aging and disease

The UPR is relevant to aging because the accumulation of damaged proteins increases as we get older. Cells gradually lose their ability to keep pace with that buildup. This plays a role in neurodegenerative diseases, diabetes and heart disease. A better understanding of how IRE1 controls this system could offer starting points for therapies that reinforce or redirect the cellular stress response.

A clearer view of a long-standing debate

The study, published in eLife, also resolves a long-running debate. Earlier research produced contradictory results about how IRE1 recognises its signal molecules. The new simulations suggest that both previously proposed mechanisms can be correct, depending on context. It is not an either-or situation but an adaptable system.

These are modelling results for now. Confirmation in living cells and organisms is the next step before this can be translated into therapeutic applications.

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