Protein Quality Control

Proteome fidelity is of critical importance in almost all cellular processes, yet it is constantly challenged by a diversity of protein aberrations arising from genetic mutations, erroneous transcription and translation, improper folding, and damage induced by various environmental stresses. A protein quality control system must sort through unlimited variations representing “bad” or “good” proteins and selectively eliminate the “bad” proteins. How can such a wide spectrum of defective proteins be captured using limited inspectors? Which molecular characteristics distinguish proteins directed to the “good” pool versus the “bad” pool? Our study addresses these long-standing fundamental questions, which have a broad impact on biology.

Protein termini are indicators of protein integrity. Discovered by Varshavsky et al. in 1986, N-degrons were the first degradation signals to be identified in short-lived proteins. In 2015, we opened a second chapter in “end-mediated” proteolysis by characterizing a C-degron pathway, by which proteins with illegitimate C-termini are eliminated. We uncovered the role of the C-degron pathway in clearing mislocalized proteins, products of proteases, and truncated selenoproteins due to translation errors. Importantly, we have provided evidence supporting that avoidance of C-degron-mediated degradation shapes eukaryotic protein evolution/selection. Accordingly, C-terminal-specific recognition for subsequent protein degradation is likely more prevalent than heretofore acknowledged. Our current research aims to identify additional functions of the C-degron pathway.

• Education
• Achievements & Honors
• Selected publications
• Lab members

• PDF, 2003-2010, Department of Genetics, Harvard Medical School, USA
• Ph.D., 2003, Department of Biology New York University, USA
• MS, 1996, Institute of Molecular Medicine, National Taiwan University
• BS, 1994, Dept. Department of Zoology, National Taiwan University

• 2011, Outstanding Scholar Awards
• 2011, Li Foundation Heritage Prize
• 2012-2016, Academia Sinica Career Development Award
• 2019-2023, Academia Sinica Investigator Award
• 2017-2022, 2022-2027, Frontier Science Grant, National Science and Technology Council

1. Yen, H.C.S., Elledge, S.J. (2008) Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science 332: 923-929.
2. Yen, H.C.S., Xu, Q., Chou, D.M., Zhao, Z., Elledge, S.J. (2008) Global protein stability profiling in mammalian cells. Science 332: 918-923.
3. Emanuele, M.J., Elia, A.E.H., Xu, Q., Thoma, C.R., Izhar, L., Leng, Y., Guo, A., Chen, Y.N., Rush, J., Hsu, W.C., Yen, H.C.S., Elledge, S.J. (2011) Global identification of modular Cullin-RING ligase substrates. Cell 147: 459- 474.
4. Lin, H.C., Ho, S.C., Chen, Y.Y., Khoo, K.H., Khoo, K.H., Hsu, P.H., Yen, H.C.S. (2015) CRL2 aids elimination of truncated selenoproteins produced by failed UGA/Sec decoding. Science 349: 91-95.
5. Chen, Y.F., Lin, H.C., Chuang, K.N., Lin, C.H., Yen, H.C.S., Yeang, C.H. (2017) A quantitative model for the rate- limiting process of UGA alternative assignments to stop and selenocysteine codons. PLoS Comput. Biol. 13: e1005367.
6. Lin, H.C., Yeh, C.H., Chen, Y.F., Lee, T.T., Hsieh, P.Y., Rusnac, D.V., Lin, S.Y., Elledge, S.J., Zheng, N., Yen, H.C.S. (2018) C-terminal end-directed protein elimination by CRL2 ubiquitin ligases. Mol. Cell 70: 602- 613.
7. Rusnac, D.V., Lin, S.C., Canzani, D., Tien, K., Hinds, T.R., Tsue, A.F., Bush, M.F., Yen, H.C.S., Zheng, N. (2018) Recognition of diglycine C-end degron by CRL2KLHDC2 ubiquitin ligase. Mol. Cell 72: 813-822.
8. Yeh, C.W., Huang, W.C., Hsu, P.H., Yeh, K.H., Wang, L.C., Hsu, W.H., Lin, H.C., Chen, Y.N., Chen, S.C., Yeang, C.H., Yen, H.C.S. (2021) The C-degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes. EMBO J. 40: e105846.
9. Hsu, Kuan-Lun, Yen, Hsueh-Chi S., and Yeang, Chen-Hsiang (2022). Cooperative stability renders protein complex formation more robust and controllable. Sci Rep 12, 10490.
10. Yeh, C. W., Hsu, K. L., Lin, S. T., Huang, W. C., Yeh, K. H., Liu, C. J., Wang, L. C., Li, T. T., Chen, S. C., Yu, C. H., Leu, J. Y., Yeang, C. H., & Yen, H. S. (2024). Altered assembly paths mitigate interference among paralogous complexes. Nature communications, 15(1), 7169.