CAT tail-directed degradation of stalled polypeptides

• Main Author: Lim, Cuithbert Jun Rong
• Other Authors: Choe Young Jun
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences
• Online Access: https://hdl.handle.net/10356/176285
• Institution: Nanyang Technological University

Ribosome-associated protein quality control (RQC) is a crucial surveillance mechanism that safeguards cellular proteostasis by promptly degrading polypeptides at stalled ribosomes during translation. Ltn1, a critical E3 ligase component of the RQC pathway, has been extensively studied for its role in mediating stalled polypeptide degradation. Upon translation stress, excessive stalled polypeptides can arise, exceeding the capacity of Ltn1. In this case, it has been proposed that C-terminal alanine and threonine tails (CAT tails), which are appended to the C-terminus of stalled polypeptides during RQC, may drive secondary Ltn1-independent degradation. In this project, I sought to investigate CAT tail-directed Ltn1-independent degradation of stalled polypeptides. I have shown that CAT-tailed stalled polypeptides can indeed be degraded by the proteasome independently of Ltn1, indicating the participation of other ubiquitin-proteasome system (UPS) components that recognise the CAT tail as a degradation signal. To identify these components, I screened 35 yeast UPS mutants for their involvement in this process. Ultimately, a total of 3 hits was obtained. Although the exact degradation mechanisms remain to be investigated further, this study suggests that eukaryotes have evolved multiple layers of degradation pathways to ensure the clearance of stalled polypeptides.