This study investigates the role of CD317 in maintaining proteostasis and cell survival in response to proteasome inhibitors (PIs). CD317, upregulated in hematological malignancies, was found to preserve proteostasis and cell viability under PI treatment. CD317 knockdown reduced ER Ca²⁺ levels, leading to PI-induced proteostasis failure and cell death. Mechanistically, CD317 interacts with calnexin (CNX), targeting it for RACK1-mediated autophagic degradation, thereby regulating Ca²⁺ uptake and ER protein folding. These findings highlight CD317's role in proteostasis and suggest it as a potential therapeutic target to overcome PI resistance.
