UFMylation, a specific type of protein modification, has been identified as critical for maintaining the balance of the endoplasmic reticulum (ER), according to a recent study published in The FASEB Journal. This research highlights the role of UFMylation in regulating the stability of BiP, a key protein involved in the cellular stress response.
Improperly folded proteins can accumulate in the ER, leading to cellular stress and increasing the risk of disorders such as type 2 diabetes, neurodegenerative diseases, and various cancers. The research team, led by Yu-Sheng Cong from Hangzhou Normal University and the University of South China, conducted in vitro experiments to investigate the impact of UFMylation on ER homeostasis.
When proteins are synthesized in cells, approximately one-third transit through the ER to achieve their functional three-dimensional structures. The ER contains three transmembrane sensor proteins that monitor protein folding. Under normal conditions, BiP prevents these sensors from aggregating. It also binds to misfolded or unfolded proteins to prevent their accumulation. However, when the burden of improperly folded proteins becomes too great, BiP detaches from the sensors, leading to their oligomerization and the activation of the unfolded protein response to restore homeostasis.
The study revealed that UFMylation plays a significant role in this process. BiP can be UFMylated at five critical sites, which marks it for degradation. When UFM1, the protein responsible for UFMylation, is expressed, ER stress is alleviated. Conversely, disrupting the enzyme involved in UFMylation leads to disturbances in ER homeostasis.
Throughout the experiments, researchers observed that UFMylation of BiP is normally maintained to regulate its levels. However, under conditions of ER stress, while UFMylation enzymes increase, they do not bind to BiP, resulting in decreased UFMylation and enhanced stability of BiP. In long-term ER stress scenarios, wild-type BiP was found to dissociate from the sensor protein, allowing cells to survive. In contrast, a mutated form of BiP, lacking its five main UFMylation sites, failed to dissociate from the sensor protein, leading to apoptosis in cells during prolonged stress.
The researchers emphasize that while further studies are necessary, their findings indicate that BiP serves as a novel substrate for UFMylation. During periods of ER stress, the reduction of UFMylation on BiP stabilizes the protein, which is crucial for maintaining ER balance.
This research was supported by the National Natural Science Foundation of China, the Zhejiang Provincial Department of Science and Technology, and the Interdisciplinary Research Project of Hangzhou Normal University.
For more details, refer to the published article, “UFMylation of BiP/GRP78 is crucial for maintenance of endoplasmic reticulum homeostasis,” available in The FASEB Journal.
About The FASEB Journal: The FASEB Journal serves as the flagship publication of the Federation of American Societies for Experimental Biology (FASEB) and is known for publishing significant multidisciplinary research across biology and biomedical sciences.
About FASEB: FASEB represents a coalition of 22 scientific member societies, totaling 110,000 members, making it the largest association of biomedical research organizations in the United States. Its mission involves promoting health and well-being through research and education in biological and biomedical sciences.
