Valosin Containing Protein (VCP): A Multistep Regulator of Autophagy

Abstract

Valosin containing protein (VCP) has emerged as a central protein in the regulation of the protein quality control (PQC) system. VCP mutations are causative of multisystem proteinopathies, which include neurodegenerative diseases (NDs), and share various signs of altered proteostasis, mainly associated with autophagy malfunctioning. Autophagy is a complex multistep degradative system essential for the maintenance of cell viability, especially in post-mitotic cells as neurons and differentiated skeletal muscle cells. Interestingly, many studies concerning NDs have focused on autophagy impairment as a pathological mechanism or autophagy activity boosting to rescue the pathological phenotype. The role of VCP in autophagy has been widely debated, but recent findings have defined new mechanisms associated with VCP activity in the regulation of autophagy, showing that VCP is involved in different steps of this pathway. Here we will discuss the multiple activity of VCP in the autophagic pathway underlying its leading role either in physiological or pathological conditions. A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs.

Keywords: NF-κB; TFE3; TFEB; VCP; autophagy; lysophagy; neurodegenerative disease.

Figure 1

VCP mutants. Graphical representation of VCP structure and localization of mutated amino acids.

Figure 2

Molecular mechanism of autophagy. Autophagy involves a series of steps including initiation, elongation, maturation, and degradation. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com (accessed 7 December 2021).

Figure 3

Overview of different roles which VCP plays in the autophagy pathway. VCP regulates autophagy and autophagic substrates degradation at different steps: (1) VCP is involved in regulating activation of transcription factors as NF-κB, TFE3, and TFEB; (2) VCP cooperates in the routing to autophagy of misfolded protein aggregates and organelles including lysosomes and mitochondria; (3) VCP enhances the formation of the PI3K complex promoting autophagy initiation; (4) VCP is involved in autophagosome maturation. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com (accessed 7 December 2021).