Ribosome Quality Control Mitigates Proteotoxic Stress in Aneuploid Cells

Abstract

Aneuploidy is widespread in tumors, but how cancer cells adapt to aneuploidy-induced cellular stresses remains poorly understood. Here, we focus on the mechanisms employed to cope with proteostasis disruption, a major stress caused by aneuploidy. We show that aneuploid cells exhibit a significant accumulation of ribosomes enclosed within autophagosomes, ultimately degraded through lysosome-mediated processes. Our data also indicate that limited folding capacity of newly synthesized polypeptides leads to lysosome-mediated degradation of ribosomes. We also found that the E3 ligase ZNF598 marks these ribosomes for degradation, thus clearing translationally-impaired ribosomes. Importantly, highly aneuploid tumors display a positive correlation with ZNF598 expression, while being negatively associated with ribosomal signatures. This suggests that ribosome-associated quality control is crucial for cancer cell survival under proteotoxic stress. Our study uncovers molecular events in response to proteotoxic stress in aneuploid cells and suggests that components of ribosome-associated quality control, including ZNF598, could serve as promising targets in cancer therapy.