26S proteasome non-ATPase subunit 3 (PSMD3)

26S proteasome non-ATPase subunit 3 (PSMD3) is a critical non-catalytic component of the 19S regulatory particle (RP) lid within the 26S proteasome complex. It serves as an essential scaffold for the assembly of the 19S RP and plays a vital role in the recognition and binding of polyubiquitinated proteins destined for degradation. By maintaining protein homeostasis, PSMD3 influences various cellular processes, including cell cycle progression, DNA repair, and apoptosis. In many malignancies, such as breast cancer, lung cancer, and multiple myeloma, PSMD3 is frequently overexpressed and correlates with poor clinical outcomes. It has been shown to stabilize key oncogenic drivers, such as HER2 and NF-κB, thereby promoting tumor cell survival and proliferation. While current clinical proteasome inhibitors like bortezomib primarily target the 20S catalytic core, PSMD3 is emerging as a promising alternative target to overcome drug resistance and reduce systemic toxicity.

Other names

RPN3P58S3TSTA2Proteasome 26S subunit non-ATPase 326S proteasome regulatory subunit RPN326S proteasome regulatory subunit S3

Inhibition of the 26S proteasome complex by disrupting the 19S regulatory particle assembly and substrate recognition.