A new paper from the Rubinsztein lab, led by Lidia Wrobel, describes how mutations in the AAA+-ATPase valosin-containing protein (VCP; also called p97 or Cdc48), can contribute to diseases such as ALS or multisystem proteinopathy. This major protein unfolding machinery has a variety of essential functions, localizing to different subcellular compartments. Currently, the processes regulating the distribution of VCP between the cytosol and nucleus are not understood. This study identified p37 (also called UBXN2B) as a major factor regulating VCP nucleocytoplasmic shuttling. p37-dependent VCP localization was crucial for local cytosolic VCP functions, such as autophagy, and nuclear functions in DNA damage repair. Mutations in VCP causing multisystem proteinopathy enhanced its association with p37, leading to decreased nuclear localization of VCP. The consequent reduction in nuclear functions makes mutant cells more prone to DNA damage. Both VCP localization and DNA damage susceptibility in cells with such mutations were normalized by lowering p37 levels. Thus, a mechanism by which VCP nucleocytoplasmic distribution is fine-tuned was revealed, providing a means for VCP to respond appropriately to local needs.