Nuclear protein localization protein 4 homolog (NPL4) (NPL4)

Nuclear protein localization protein 4 homolog (NPL4) is a key adapter protein that functions as a subunit of the VCP/p97 segregase complex, a central player in the ubiquitin-proteasome system (UniProt Q8TAT6). Together with UFD1, NPL4 forms a heterodimer that recognizes and binds polyubiquitinated substrates, enabling the p97 ATPase to extract them from cellular structures like the endoplasmic reticulum or chromatin for degradation (PubMed: 34262183). This activity is essential for diverse processes, including endoplasmic reticulum-associated degradation (ERAD), DNA replication, and the maintenance of genomic stability (UniProt Q8TAT6). NPL4 is often upregulated in various malignancies, such as clear cell renal cell carcinoma and bladder cancer, where it helps tumor cells manage high levels of proteotoxic stress (PubMed: 32670254, PubMed: 31109319). The drug disulfiram, traditionally used for alcohol aversion, has been repurposed as an anticancer agent because its metabolite, CuET, specifically targets NPL4 (Nature 552, 194). CuET induces the aggregation and immobilization of NPL4 by disrupting its zinc finger motifs, thereby crippling the VCP/p97 complex and triggering apoptosis through the accumulation of misfolded proteins (Nature 552, 194).

Other names

NPLOC4KIAA1499HRD4Protein NPL4Nuclear protein localization 4 homolog

Disulfiram's metabolite CuET (bis-diethyldithiocarbamate-copper) binds to and disrupts the zinc finger motifs of NPL4, causing the protein to aggregate and immobilize within the cell (Nature 552, 194). This immobilization inhibits the VCP/p97 segregase complex, preventing the extraction and subsequent proteasomal degradation of ubiquitinated proteins (PubMed: 29239351). The resulting accumulation of polyubiquitinated proteins triggers massive proteotoxic stress, the heat-shock response, and the unfolded protein response, ultimately leading to cancer cell death via apoptosis or pyroptosis (PubMed: 34262183).