Academia Sinica Logo

This study was conducted by the research team led by Dr. Hsueh-Chi S. Yen at the Institute of Molecular Biology, Academia Sinica. The team has long focused on understanding how proteins are degraded within cells, and how these processes influence health and disease.

Proteins are the core functional molecules of cells, and even small changes at the “tail end” (C-terminus) of a protein can significantly affect its lifespan. This study shows that when proteins undergo disease-associated nonstop mutations, alternative splicing, or translational readthrough, their C-terminal sequences can be altered. Traditionally, such abnormal C-termini were believed to make proteins more prone to degradation. However, this research challenges that conventional view by demonstrating that certain abnormal C-termini can instead stabilize proteins and extend their lifespan.

The team further identified multiple cancer-related proteins—including oncogenes and tumor suppressors—whose stability is altered by C-terminal variations. The study also reveals that C-termini enriched in hydrophobic residues are more likely to be recognized and regulated by the cell’s protein quality control and degradation machinery. These findings suggest that the protein tail is not merely a degradation signal, but also a regulatory module that cells can exploit to fine-tune protein function.

The research was published on February 3, 2026, in Nature Communications, under the title “Protein C-terminal variations impact proteostasis”, and was selected as a Featured Article. This work was supported by Academia Sinica and the National Science and Technology Council of Taiwan.

Authors: Ching-Yu Chu (GSB program), Shu-Yu Hsu (GSB program), Chi-Wei Yeh, Kun-Hai Yeh (Senior Bioinformatician), Li-Chin Wang (GSB program), Lo-Tung Lee, Shu-Chuan Chen, Chen-Hsin Yu (Core manager), Hsueh-Chi S. Yen.