Proteostasis is maintained by the coordinated action of the ubiquitin–proteasome system (UPS) and autophagy–lysosome pathways. Valosin-containing protein (VCP/p97), an AAA+ unfoldase, sits at its intersection by extracting ubiquitinated clients and assembling cofactor-defined complexes that determine substrate fate. In cancer, VCP up-regulation and altered cofactor recruitment rewire these ubiquitin-dependent routing decisions. By recruiting E3 ligases and deubiquitinases that remodel K48- and K63-linked ubiquitin chains, VCP biases substrates toward Ufd1–Npl4–coupled proteasomal turnover or autophagy-linked clearance, enabling oncogene stabilization or tumor suppressor loss. These principles are reflected in cancer axes that modulate autophagy flux, invasion and metastasis, PI3K/AKT/mTOR signaling, and immune evasion. The tumor suppressor p53 illustrates this complexity with state-dependent outcomes: VCP promotes proteasomal turnover of wild-type p53 through the canonical Ufd1–Npl4 complex, whereas it can stabilize the R273H hotspot mutant in a chaperone/holdase-like manner, prolonging gain-of-function phenotypes. Opposing regulators further control VCP function: PLAC8 enhances VCP–Ufd1–Npl4 activity and is linked to wild-type p53 turnover, PI3K/AKT/mTOR activation, and context-dependent autophagy effects. In contrast, SVIP can outcompete other VCP cofactors and, via acylation-dependent membrane targeting, redirect VCP toward lysosome-associated functions with predominantly tumor-suppressive effects. Collectively, this framework motivates therapeutic strategies that modulate VCP–cofactor interactions to regulate substrate degradative fate. Approaches include disrupting the Ufd1–Npl4 axis, biasing VCP from UPS to autophagy, altering subcellular localization, and reprogramming VCP for targeted proteolysis, with implications for cancer, fibrosis, neurodegeneration, and multisystem proteinopathy.
Hitchman et al. (Fri,) studied this question.