Proteasome 26S subunit, non-ATPase 14 (PSMD14)

Proteasome 26S subunit, non-ATPase 14 (PSMD14) is a zinc-dependent metalloprotease and a critical deubiquitinating enzyme within the 19S regulatory particle of the 26S proteasome, responsible for removing polyubiquitin chains from targeted substrates prior to their degradation by the proteasome’s 20S core. This function is essential for regulated protein turnover, cellular homeostasis, and quality control. PSMD14 specifically recognizes and cleaves Lys-63-linked ubiquitin chains and thereby regulates diverse cellular processes, including cell cycle progression, apoptosis, DNA double-strand break repair, and multiple oncogenic signaling pathways. Aberrant activity or expression of PSMD14 has been implicated in cancer progression, multidrug resistance, and neurodegenerative disorders. While PSMD14 is considered a promising therapeutic target—especially for certain cancers—no selective, clinically approved inhibitors exist as of 2024, and broad proteasome inhibition can lead to significant toxicity due to interference with essential cellular protein degradation

Other names

26S proteasome non-ATPase regulatory subunit 1426S proteasome regulatory subunit Rpn11POH1PAD1RPN11proteasome (prosome, macropain) 26S subunit, non-ATPase, 14testis tissue sperm-binding protein Li 69n

Inhibition of PSMD14’s deubiquitinase (metalloprotease) activity prevents deubiquitination and leads to accumulation of polyubiquitinated proteins, impaired proteasomal degradation, cell cycle arrest, and apoptosis, with anti-tumor effects in preclinical models