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

26S proteasome non-ATPase regulatory subunit 4 (PSMD4), also known as Rpn10 or S5a, is a critical component of the 19S regulatory particle of the 26S proteasome [1, 4]. It functions as a primary ubiquitin receptor, utilizing its ubiquitin-interacting motifs (UIMs) to recognize and bind polyubiquitinated proteins, facilitating their entry into the catalytic core for degradation [3, 4]. This process is essential for maintaining cellular protein homeostasis and regulating key pathways such as the cell cycle, apoptosis, and DNA damage repair [2, 4]. In various cancers, including multiple myeloma and colorectal cancer, PSMD4 is often overexpressed and correlates with poor prognosis and resistance to standard proteasome inhibitors like bortezomib [5, 13, 25]. Consequently, PSMD4 has emerged as a promising therapeutic target; specific inhibitors like SB699551 have been developed to block its ubiquitin-binding function, triggering apoptosis in malignant cells while potentially overcoming resistance to existing therapies [5, 17]. However, because PSMD4 is vital for normal cellular function and its knockout is lethal in mammalian models, therapeutic strategies must carefully balance efficacy against the risk of systemic toxicity [6, 18].

Other names

Rpn10S5aAFAF-1ASFMCB1pUB-R5Proteasome 26S subunit ubiquitin receptor non-ATPase 4

Inhibition of polyubiquitin chain binding to the 19S regulatory particle by targeting the ubiquitin-interacting motifs (UIMs) of PSMD4, leading to the accumulation of ubiquitinated proteins and induction of apoptosis.