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When improperly folded proteins build up in the endoplasmic reticulum (ER), cells become stressed and conditions such as type 2 diabetes, neurodegenerative disorders, and cancers can develop. In a recent study in The FASEB Journal, researchers found that a modification known as UFMylation plays an important role in reducing ER stress and maintaining homeostasis by altering the stability of a protein called BiP in cells. A better understanding of this process could help scientists develop improved treatments.

About a third of the proteins made in a cell move through the ER to achieve their proper 3D structures. Three ER transmembrane sensor proteins keep track of protein folding. Under normal conditions, BiP keeps the sensors from clumping together. BiP also binds misfolded or unfolded proteins in the ER to keep them from aggregating. But when too many improperly folded proteins are present, BiP leaves the sensors, which oligomerize and activate the unfolded protein response to restore balance.

Studies have shown that a protein modification known as UFMylation could be involved. With UFMylation, a protein called UFM1 is covalently attached to other proteins, marking them for degradation. UFM1 expression relieves ER stress, whereas a knockout of an enzyme involved in UFMylation disrupts ER homeostasis.

To learn more about UFMylation's role in ER homeostasis, Yu-Sheng Cong and colleagues at Hangzhou Normal University and the University of South China conducted a series of in vitro experiments.

The researchers showed that BiP could be UFMylated at five main sites, causing it to be degraded. In other experiments, the team found that cells treated with ER stress-inducing compounds had elevated levels of enzymes and factors that are involved in UFMylation.

Through a series of experiments, the researchers found that BiP levels are normally kept in check with UFMylation. However, when the ER is under stress, UFMylation enzymes increase but no longer bind BiP, and BiP becomes less UFMylated and more stable. Under long-term ER stress, wild-type BiP dissociated from a sensor protein in binding experiments and cells lived. A form of BiP with its five main UFMylation sites mutated did not dissociate from the sensor protein, and cells expressing this BiP underwent apoptosis during prolonged stress.

Although the researchers say more work is needed, they conclude that BiP is a novel substrate for UFMylation and during ER stress, BiP UFMylation is reduced and the protein is stabilized. "Our findings suggest that the UFMylation of BiP is critical for maintaining ER homeostasis," say the authors.