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.
Highlights
Neurodegenerative diseases (NDs) are heterogeneous, frequently fatal and caused by the loss of neurons in different regions of the central or peripheral nervous system (CNS or PNS, respectively)
Some reports showed an opposite effect of Valosin containing protein (VCP) in autophagy in which the inhibition of VCP leads to SQSTM1/p62 degradation that is reverted by autophagy inhibition with Bafilomycin A, a late-step autophagy inhibitor is reverted by autophagy inhibition with Bafilomycin A, a late-step autophagy inhibitor supporting the inhibitory role of VCP in the autophagic pathway [127]
VCP is involved in different steps of the autophagic process as: autophagy activation by concurring in the regulation of the transcription factors NF-κB, transcription factors EB (TFEB) and TFE3; autophagy initiation by promoting the formation and stabilization of ATG14-Vps34-Vps15-BECN1 complex resulting in increased PtdIns3P levels; and autophagy maturation by cooperating in autophagosome and lysosome fusion through a still unknown mechanism
Summary
Neurodegenerative diseases (NDs) are heterogeneous, frequently fatal and caused by the loss of neurons in different regions of the central or peripheral nervous system (CNS or PNS, respectively). Chaperones are proteins that, by cooperating with co-chaperones, are involved in the recognition of unfolded or misfolded proteins Their role is based on supporting the proper folding of unfolded or misfolded proteins and, when this fails, on enhancing their clearance [3,4]. Valosin containing protein (VCP) is a chaperone-like protein, encoded by the VCP gene in humans, that has various roles in the PQC system being involved both in UPS and autophagy. 2 of has 18 a well-established role in enhancing misfolded protein degradation through the UPS, whereas VCP functions in autophagy are still not fully defined [5]. VCP has a wellknowledge on activity in this pathway could help in understanding the pathological established role in enhancing misfolded protein degradation through the UPS, whereas mechanisms possibly opening new approaches.
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