VCP/97 NUCLEOCYTOPLASMIC TRANSPORT IN PHYSIOLOGY AND NEURODEGENERATION

The AAA⁺-ATPase valosin-containing protein (VCP; also called p97 or Cdc48), a major protein unfolding machinery with a variety of essential functions, localizes in the cytosol and in the nucleus. Precise VCP localisation has a profound impact on the regulation of localised VCP-mediated functions and ability of cells to respond to stress. However, the processes regulating the distribution of VCP between the cytosol and nucleus were not understood. Recently, we 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. Dominant mutations in VCP, causing frontotemporal dementia (FTD), enhanced its association with p37, leading to decreased nuclear entry of VCP, which enhanced susceptibility to DNA damage accumulation. Both VCP localization and DNA damage sensitivity in neurons with such mutations were normalized by lowering p37 levels. Thus, we uncovered a mechanism by which VCP nucleocytoplasmic distribution is fine-tuned, providing a means for VCP to respond appropriately to local needs. These observations open new perspectives on the mechanisms underlying FTD, suggesting that in neurons carrying VCP mutations, part of the pathology may arise from the inability of VCP to maintain proper intracellular compartmentalization and thus from impaired neuronal stress-response mechanisms.