Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system

Abstract

The ATP-driven chaperone valosin-containing protein (VCP)/p97 governs critical steps in ubiquitin-dependent protein quality control and intracellular signalling pathways. It cooperates with diverse partner proteins to help process ubiquitin-labelled proteins for recycling or degradation by the proteasome in many cellular contexts. Recent studies have uncovered unexpected cellular functions for p97 in autophagy, endosomal sorting and regulating protein degradation at the outer mitochondrial membrane, and elucidated a role for p97 in key chromatin-associated processes. These findings extend the functional relevance of p97 to lysosomal degradation and reveal a surprising dual role in protecting cells from protein stress and ensuring genome stability during proliferation.

Control of p97 function by cofactor binding

“…p97 can interact with a large number of cofactors that regulate its function by recruiting it to different cellular pathways [5,17,44]. So far, about 40 cofactors have been identified in mammals, and the number is still growing.…”

“…Importantly, these binding modes provide the structural basis for the mutually exclusive binding of p47 (and its homologues) and UFD1-NPL4 to p97 [50,101], which is evolutionarily conserved and defines the two best-characterized p97 assemblies with distinct cellular functions. The p97 UFD1-NPL4 complex is required in a number of proteasomal degradation pathways such as ERAD, where it drives the dislocation of polyubiquitylated substrates from the ER membrane into the cytosol, degradation of proteins associated with chromatin and the outer mitochondrial membrane, and of important regulators of cell cycle progression and signal transduction (reviewed in [5,[17][18][19]). In contrast, the p97 p47 complex functions mainly in proteasome-independent processes such as autophagy and the post-mitotic reassembly of Golgi stacks and the nuclear envelope [5,17,106].…”

“…Finally, we will discuss the impact of disease-causing VCP mutations on the structure of p97 and its interactions with cofactors. More detailed information about the cellular functions of p97 can be found in several recent reviews [5,[17][18][19].…”

“…Since p97 is involved in highly diverse cellular processes, its segregase activity must be tightly controlled in time and space. This is achieved by a host of regulatory cofactors, which control substrate specificity and fate, subcellular localization and the oligomeric state of p97 [5,13,14]. In fact, the number and diversity of p97 cofactors is unique among the AAA ATPases, making p97 a prime example of a modular system comprising a relatively unspecific ''engine" and a sophisticated ''tool-kit" for specific cellular tasks.…”

“…p97 is involved in the proteasomal degradation of protein quality control targets, cell cycle regulators, transcription factors and DNA repair proteins, but also in non-proteasomal proteolysis through macroautophagy and the endolysosomal pathway [5,6]. Moreover, p97 mediates the nonproteolytic mobilization of ubiquitylated proteins, e.g.…”