Bclaf1 biomolecular condensates protect nuclear PTK2 from ubiquitin-proteasome system promoting cardiomyocyte survival during oxidative stress

PTK2, a non-receptor tyrosine kinase, plays a critical role in regulating essential cellular functions, including cell survival, by reducing p53 levels and activating the PI3K/AKT pathway. However, the mechanism underlying PTK2 stabilization during stress remained unclear. Here, we identified Bclaf1, a multifunctional protein known to stabilize partners, as a PTK2 interactor. Using advanced microscopy techniques, we identified nuclear Bclaf1 biomolecular condensates containing PTK2 in cardiomyocytes under oxidative stress. While PTK2 diffused through the nucleus was susceptible to ubiquitination, PTK2 sequestered in the Bclaf1 condensates was protected from the ubiquitin-proteasome system (UPS). The PTK2 ubiquitination site K926 was identified, and proteasome inhibition confirmed the UPS role in PTK2 homeostasis. Furthermore, disrupting Bclaf1 biomolecular condensates leads to PTK2 degradation, subsequently increasing p53 levels and activating apoptosis. Our findings support the role of Bclaf1 driving the formation of pro-survival nuclear condensates that sequester and stabilize PTK2, promoting cardiomyocyte survival during oxidative stress.