VCP D1 ATPase activation enhances both autophagic and proteasomal neurotoxic protein clearance

Autophagy upregulation enhances the clearance of various neurotoxic proteins and ameliorates their toxicities in disease models. Thus, autophagy activators may have therapeutic utility. Here, we have identified the essential protein VCP/p97 as a target of the autophagy-inducing molecule SMER28, providing a mechanism for a molecule that has shown promising results in animal models of neurodegeneration. SMER28 stimulates VCP D1 ATPase activity to activate autophagy by enhancing interactions of PI3K complex components to increase PI(3)P production and consequent autophagosome formation. Interestingly, SMER28-mediated increase in VCP D1 ATPase activity also enhances degradation of short-lived misfolded and aggregate-prone proteins through the ubiquitin-proteasome system (UPS). We further show that another recently described activator of VCP induces autophagy and UPS flux in a comparable manner, providing additional evidence that targeting VCP D1 ATPase domain could be a useful approach for clearance of aggregate-prone proteins by both autophagy-lysosome and proteasomal routes.