26S proteasome non-ATPase regulatory subunit 14 (PSMD14) (PSMD14)

26S proteasome non-ATPase regulatory subunit 14 (PSMD14), also known as POH1 or Rpn11, is a critical zinc-dependent metalloprotease located within the 19S regulatory particle of the 26S proteasome (UniProt O00487). It belongs to the JAMM (JAB1/MPN/Mov34 metalloenzyme) family of deubiquitinating enzymes and is responsible for the essential step of removing polyubiquitin chains from substrates as they are translocated into the 20S catalytic core for degradation (PubMed: 29033320). By facilitating the recycling of ubiquitin and the unfolding of target proteins, PSMD14 maintains cellular protein homeostasis and prevents the accumulation of toxic protein aggregates (PubMed: 28190769). In many human cancers, including multiple myeloma and hepatocellular carcinoma, PSMD14 is frequently overexpressed, which promotes the degradation of tumor suppressors and helps malignant cells survive high levels of proteotoxic stress (PubMed: 28190769, PubMed: 28423570). Consequently, PSMD14 has emerged as a significant therapeutic target; small-molecule inhibitors like capzimin have been developed to block its metalloprotease activity, thereby inducing apoptosis in cancer cells by disrupting the proteasome-ubiquitin pathway (PubMed: 31104953). This approach provides a distinct mechanism of action compared to traditional 20S proteasome inhibitors like bortezomib, potentially overcoming resistance in clinical settings (PubMed: 31104953, PubMed: 28423570).

Other names

POH1Rpn1126S proteasome regulatory subunit RPN1126S proteasome non-ATPase subunit 1419S proteasome JAMM-domain deubiquitinase

Inhibition of the JAMM-domain metalloprotease activity to prevent substrate deubiquitination and subsequent proteasomal degradation.