Valosin-containing protein (VCP): structure, functions, and implications in neurodegenerative diseases

Abstract

Valosin-containing protein (VCP) is a hexameric protein belonging to the type II AAA+ (ATPases Associated with diverse cellular Activities) protein family. VCP governs multiple cellular processes and its diverse functions are determined by its interaction with a wide variety of partners and cofactors. Recently, mutations in VCP were suggested to cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease. However, the pathogenic mechanisms of VCP mutations in these diseases are still largely unknown. In this review, we summarize the structure and cellular functions of VCP, especially focusing on apoptosis and two major cellular degradation pathways, the ubiquitin-proteasome system and autophagy. We also list the representative VCP mutations and discuss their potential association with neurodegenerative diseases. ARTICLE HISTORY

A small-molecule ligand of valosin-containing protein/p97 inhibits cancer cell–accelerated fibroblast migration

“…This study shows that NPD8733 inhibits the enhanced migration of co-cultured NIH3T3 cells by binding to VCP, a ubiquitously expressed protein that belongs to the AAAϩ protein family. VCP is involved in multiple cellular processes, such as protein degradation, apoptosis, and autophagy (15)(16)(17). Although there are no reports that show involvement of VCP in the activation of fibroblast migration, VCP is known to play an important role in osteosarcoma cell metastasis through proteasome-dependent degradation of IB␣, thus activating NF-B␣ (21).…”

“…VCP, also referred to as p97, consists of four domains, including the N-terminal domain, the two ATPase domains D1 and D2, and the unstructured C-terminal tail (15,24). The N-terminal domain and C-terminal domain are known to be important for binding to substrates and co-factors involved in a variety of cellular functions (15), whereas the D1 and D2 domains encode ATPase catalytic domains. Although both D1 and D2 can hydrolyze ATP, they differ in terms of activity.…”

“…We have shown that NPD8733 bound to the D1 domain of VCP. The D1 domain of VCP has minor ATPase activity and is also known to be involved in oligomerization for hexamer formation, which occurs after ATP hydrolysis (15). This oligomerization has been reported to be essential for protein degradation upon endoplasmic reticulum (ER) stress (17).…”

“…VCP is a ubiquitously expressed protein that belongs to the ATPase-associated with diverse cellular activities (AAAϩ) protein family. VCP is involved in many cellular processes, such as protein degradation, apoptosis, and autophagy (15)(16)(17). To date, there are no reports defining the role of VCP in the activation of fibroblasts.…”

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

“…In addition, a recent study has shown that an ATPase protein named valosin-containing protein (VCP) is involved in the regulation of mitochondrial Ca 2+ uptake [ 13 ]. VCP belongs to an ATPase associated family with four structural domains [ 87 ]: an N-terminal substrate-binding domain, two ATPase domains, and a C terminal domain. It has been shown that VCP is involved in multiple cellular pathways in many tissues such as autophagy, apoptosis, and ubiquitin degradation [ 88 ].…”