Unfolded proteins (red) in the endoplasmic reticulum recruit BiP (blue) to help fold them, preventing this chaperone from binding IRE1 (green), which can then signal to produce more BiP (left). As unfolded protein levels decrease, BiP is free to bind IRE1 and stop it from signalling, decreasing the production of BiP (right). Image credit: adapted from Claudia Flandoli (CC BY 4.0)
Cells produce many protein molecules. These are made of chains of building blocks called amino acids that then fold into three-dimensional shapes. Specialist proteins known as chaperones assist this folding process. For example, the chaperone BiP helps other proteins fold in a compartment within the cell called the endoplasmic reticulum.
To match the supply of chaperones to the demand of unfolded proteins, cells have stress receptors, such as IRE1 in the endoplasmic reticulum. IRE1 responds to changing levels of unfolded proteins by generating signals that tell cells whether they need more chaperones. Previous studies in a test tube suggest that when levels of unfolded proteins are low, BiP represses IRE1 signalling. However, when the levels of unfolded proteins increase, the unfolded proteins compete with IRE1 for BiP, releasing the brake BiP imposes on IRE1 signalling. It remained unclear if BiP regulates IRE1 in the same way in living cells.
To address this question, Amin-Wetzel, Neidhardt et al. studied IRE1 signalling in mammalian cells grown in the laboratory. The experiments revealed that cells containing a modified version of IRE1 to which BiP binds more strongly had less IRE1 signalling. On the other hand, cells containing versions of IRE1 that BiP binds less well had more active IRE1 signalling. These findings suggest that in cells, as in the test tube, unfolded proteins and IRE1 compete for BiP binding. This relationship comprises a simple mechanism allowing cells to sense and respond to the burden of unfolded proteins in their endoplasmic reticulum.
Over time, the amount of unfolded proteins in the cell likely contributes to the development of aging-related diseases such as adult-onset diabetes. A better understanding of how cells handle unfolded proteins may lead to more effective treatments for these diseases.
