Research uncovers how 'reubiquitination' promotes elimination of misfolded membrane proteins

Chinese researchers recently discovered a protein quality control mechanism called "reubiquitination". The mechanism, according to the researchers, could promote the elimination of misfolded membrane proteins, minimize their dwell time in cells, and thereby reduce their probability to form toxic aggregates in human body.

Discovered by a research team from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences, the "reubiquitinase" RNF126 adds a small protein called ubiquitin to the unfolded membrane protein intermediates in the cytosol, and targets them to the degradation machinery, proteasome, for destruction.

Misfolded proteins in cells and organisms should be cleared by a protein quality control mechanism called ubiquitin-proteasome system. If not, they tend to form pathological aggregates that are believed to damage cells (e.g., neurons), and ultimately cause various diseases of aging, such as neurodegeneration.

The results show that RNF126-mediated reubiquitination is important for normal cell physiology. Without reubiquitination, targeting of misfolded proteins to the proteasome could be delayed, and this increase the risk of protein aggregation and cellular stress, which could gradually lead to various diseases.

In addition, the function of RNF126 as a reubiquitinase might be required for rapid proliferation of certain cancer cells, making it a potential therapeutic target.

This work has been published online in July 8, 2020 in Molecular Cell, and it was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, and the Shanghai Municipal Science and Technology Major Project.

Source:
Journal reference:

Zhang, Z., et al. (2020) RNF126-mediated reubiquitination is required for proteasomal degradation of p97-extracted membrane proteins. Molecular Cell. doi.org/10.17632/w99dh6rymx.1.

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