Wrobel Lidia, Hoffmann Johanna L, Li Xinyi, Rubinsztein David C
Department of Medical Genetics, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Sci Adv. 2024 May 3;10(18):eadl6082. doi: 10.1126/sciadv.adl6082.
The AAA-ATPase valosin-containing protein (VCP; also called p97 or Cdc48), a major protein unfolding machinery with a variety of essential functions, localizes to different subcellular compartments where it has different functions. However, the processes regulating the distribution of VCP between the cytosol and nucleus are not understood. Here, 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. Mutations in VCP causing multisystem proteinopathy enhanced its association with p37, leading to decreased nuclear localization of VCP, which enhanced susceptibility to DNA damage accumulation. Both VCP localization and DNA damage susceptibility in cells 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.
AAA-ATP酶含缬酪肽蛋白（VCP；也称为p97或Cdc48）是一种具有多种重要功能的主要蛋白质解折叠机制，定位于不同的亚细胞区室，在那里它具有不同的功能。然而，调节VCP在细胞质和细胞核之间分布的过程尚不清楚。在这里，我们确定p37（也称为UBXN2B）是调节VCP核质穿梭的主要因素。p37依赖的VCP定位对于局部细胞质VCP功能（如自噬）和DNA损伤修复中的核功能至关重要。导致多系统蛋白病的VCP突变增强了其与p37的结合，导致VCP核定位减少，从而增加了对DNA损伤积累的易感性。通过降低p37水平，具有此类突变的细胞中的VCP定位和DNA损伤易感性均恢复正常。因此，我们揭示了一种微调VCP核质分布的机制，为VCP提供了一种对局部需求做出适当反应的方式。
