26S proteasome non-ATPase regulatory subunit 4 (PSMD4) (PSMD4)

26S proteasome non-ATPase regulatory subunit 4 (PSMD4), also known as Rpn10 or S5a, is a key ubiquitin receptor within the 19S regulatory particle of the 26S proteasome (UniProt P55036). It functions by recognizing and binding polyubiquitinated proteins through its ubiquitin-interacting motifs (UIMs), facilitating their delivery to the catalytic core for degradation (PubMed: 10490618). PSMD4 is essential for maintaining cellular protein homeostasis, and its dysregulation is linked to various cancers, most notably multiple myeloma and hepatocellular carcinoma, where its overexpression correlates with poor prognosis and resistance to conventional proteasome inhibitors (PubMed: 28416776, 31110014). Targeting PSMD4 mRNA using RNA interference (RNAi) or antisense oligonucleotides (ASOs) is an emerging therapeutic approach designed to deplete the protein and disrupt the ubiquitin-proteasome system in malignant cells (PubMed: 16123311). This strategy aims to induce proteotoxic stress and subsequent apoptosis in cancer cells that are heavily reliant on efficient protein clearance. While promising, the therapeutic application of PSMD4-targeting agents faces challenges such as achieving efficient delivery to tumor sites and minimizing systemic toxicity associated with broad proteasome inhibition (PubMed: 25635005).

Other names

Rpn10S5aMCB1P54AFAF-1ANGELp54Proteasome 26S subunit, non-ATPase 4

RNA interference or antisense-mediated degradation of PSMD4 mRNA, leading to reduced PSMD4 protein levels and subsequent inhibition of ubiquitin-dependent protein degradation.