Nuclear protein localization protein 4 cofactor–valosin-containing protein segregase complex (NPL4–p97/VCP segregase complex)

The nuclear protein localization protein 4 cofactor–valosin-containing protein segregase complex is a multi-protein assembly central to eukaryotic cellular proteostasis. The core consists of valosin-containing protein (VCP), also known as p97—a highly conserved AAA+ ATPase—and its major adaptors/cofactors NPLOC4 (nuclear protein localization homolog) and UFD1L. This ternary “segregase” uses energy from ATP hydrolysis to extract ubiquitinated substrates from membranes, chromatin, ribosomes, or large macromolecular assemblies so they can be degraded by the proteasome. The process is essential for endoplasmic reticulum-associated degradation (ERAD), mitochondrial quality control, DNA replication/repair regulation during cell cycle progression, membrane fusion events after mitosis, and more. Dysfunctional activity—whether through mutation or pharmacologic inhibition—can result in severe pathologies including neurodegeneration and cancer susceptibility/resistance due to altered clearance capacity for misfolded/damaged proteins.[1][2][3][5]

Other names

NPL4–VCP complexNPL4–p97 complexUfd1-Npl4-p97 complexValosin-containing protein (VCP)/p97 segregase adaptor NPL4[3][5]p97-Ufd1-Npl4 complex[5]

Disulfiram/CuET: - Induces clustering/aggregation of NPL4, leading to dysfunction of the VCP/p97 segregase pathway. - Causes accumulation of polyubiquitinated proteins due to impaired extraction/degradation. - Results in proteotoxic stress selectively toxic to cancer cells with high proteasome dependency.[3] Other potential mechanisms: - Inhibition or modulation of ATP hydrolysis or adaptor binding could disrupt substrate processing.