P16INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination

• Published in: iScience 2024-10, Vol.27 (10), p.110882, Article 110882
• Main Authors: Weng, Wenjie, Zhang, Baozhen, Deng, Dajun
• Format: Article
• Language: English
• Subjects: Cellular physiology; Functional aspects of cell biology; Molecular interaction; Molecular physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110882

P16INK4A expression is inversely associated with RB1 expression in cancer cells, and P16INK4A inhibits CDK4-catalyzed RB1 phosphorylation. How P16INK4A and RB1 coordinately express and regulate the cell cycle remains to be studied. In the present study, we found that P16INK4A upregulated the E3 ligase UTP14A, which led to the ubiquitination of RB1 at K810 and RB1 degradation. P16INK4A loss consistently disrupted the UTP14A-mediated degradation of RB1 and caused RB1 accumulation. Functionally, P16INK4A loss inhibited RB1 ubiquitination in a cell cycle progression-independent fashion and inhibited proteome-scale ubiquitination in a cell cycle progression-dependent manner. Our findings indicate that there is a negative feedback loop between P16INK4A and RB1 expression and that disruption of this loop may partially rescue the biological outcomes of P16INK4A loss. We also revealed a hitherto unknown function for P16INK4A in regulating proteome-scale ubiquitination by inhibiting cell proliferation, which may be useful for the development of anticancer drugs. [Display omitted] •We discovered that P16INK4A drives RB1 degradation through ubiquitination at K810•We found that the E3 UTP14A is essential for P16INK4A-mediated RB1 degradation•We revealed that P16INK4A reduces UTP14A degradation•Loss of P16 enhances RB1 accumulation in a cell cycle-independent fashion Cellular physiology; Molecular physiology; Molecular interaction; Functional aspects of cell biology