Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

Abstract

In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM- and ATR-mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons, sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict.

Keywords: DNA damage response; ERAD; SUMOylation; apoptosis; autophagy; cell cycle control; genetic diagnosis; genotype–phenotype correlation; lysophagy; mitophagy; multisystem proteinopathy; neuron; osteoclast; skeletal muscle; stress granules; ubiquitination; valosin-containing protein.

Figure 1

Diverse functions of cytosolic VCP in the proteasome and autophagy systems. (A) Lysophagy: VCP responds to lysosomal damage with cofactors PLAA, UBXD1 and YOD1, preparing the lysosome for recruitment to the phagophore. (B) Mitophagy: VCP is recruited to depolarized mitochondria with UBXN1 and UBXD1 cofactors to extract MFN2 to facilitate fragmentation of depolarized mitochondria in preparation for mitophagy, and VCP interacts with VPS13D to regulate the tethering of the ER to mitochondria. (C) ERAD: VCP and cofactors UFD1 and NPL4 extract misfolded proteins from the ER, extracted proteins are degraded by the proteasome. (D) Stress granules: VCP cofactors UFD1 and PLAA degrade defective ribosomal products during polysome disassembly, which plays a role in stress granule assembly. ZFAND1 recruits VCP and 26S proteasome to stress granules for their clearance by autophagy. (E) Autophagic flux: The phagophore buds off from the omegasome of the ER and defective proteins and organelles are recruited to the growing phagophore. The phagophore closes around the cellular waste as ATG proteins are recruited and removed from the membrane. The mature autophagosome fuses with the lysosome, forming the autolysosome where contents are degraded. VCP may be implicated in autophagosome maturation, although the precise mechanisms have yet to be elucidated. The arrows from panels A, B and D indicate that dysfunctional proteins, organelles and stress granules are recruited to the growing autophagosome.

Figure 2

The interactions of VCP with mitochondrial proteins. The figure represents the functions of VCP associated with mitochondria, with arrows indicating interactions between proteins. (A) UFD1 and NPL4 first complex with VCP and before being recruited to a multitude of outer mitochondrial membrane proteins which are extracted for proteasomal degradation in the cytosol while also regulating mitophagy. (B) VCP cofactors UBXN1/SASK1 and p47 bind to VCP. This complex is associated with degradation of MFN1/MFN2, which is mediated through contact with PINK1, andh leads to a decrease in mitochondria–ER contact sites. (C) VCP binds with UBXD1/UBXN6 leading to degradation of MCL1, causing loss of mitochondrial membrane potential. (D) VCP can target the MITOL/March5, which leads to detachment from the mitochondrial outer membrane and association with peroxisomes. The question mark indicates that we currently do not know which VCP cofactors/adaptors bind to VCP to facilitate this interaction.

Figure 3

Diverse functions of nuclear VCP in the DNA repair pathways. (A) VCP in nucleotide excision repair, (B) VCP in ATR-mediated DNA damage response, (C) VCP in ATM-mediated DNA damage response, (D) VCP in non-homologous end joining and (E) VCP in homologous recombination.