Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare d…

Abstract The cellular response to lysosomal damage involves fine-tuned mechanisms of membrane repair, lysosome regeneration and lysophagy, but how these different processes are coordinated is not fully understood. Here we show in human cells that the deubiquitinating enzyme ATXN3 helps restore integrity of the lysosomal system after damage by targeting K48-K63-linked branched ubiquitin chains on regenerating lysosomes. We find that ATXN3 translocates to lysosomes after different types of damage and there colocaliz…

We present symmetric multivalent tweezers as the first class of supramolecular elements designed to cover and functionally block a protein pore. As a model, we chose the enzyme p97, a hexameric AAA-ATPase that unfolds or segregates substrate proteins by threading them through a pore and channel at the center of the symmetric p97 hexamer fueled by ATP hydrolysis. In a rational design approach, we developed a new class of p97 inhibitors, guided by molecular modeling. These dock onto lysine residues at the entry of t…

Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare d…

Lysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the in…