p97, also known as VCP, is an abundant and highly conserved AAA+ (ATPases associated with diverse cellular activities) ATPase that is crucial for maintaining cellular proteostasis. In addition to extracting proteins from membranes or molecular complexes for proteasomal degradation, p97 also plays key roles in lysosomal degradation through autophagy and endolysosomal sorting, membrane fusion, and the regulation of intracellular signaling, cell proliferation, and survival. These various cellular processes are propelled by the chemical energy released during ATP hydrolysis and are coordinated by p97's interactions with up to 40 cofactors, which direct it to specific subcellular sites and substrates for their processing and remodeling.
Numerous neurodegenerative diseases have been linked to p97 mutations, and overexpression of p97 in its wild-type is seen in many cancers. In addition, it has been demonstrated that p97 activity is necessary for the replication of a number of viruses, including influenza, poliovirus, herpes simplex virus, cytomegalovirus, and herpes simplex virus (HSV). These findings point to the possibility of using p97 targeting as a therapeutic strategy for neurodegeneration, cancer, and some infectious diseases.
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