Valosin 含蛋白 (VCP)，也称为 p97，是一种进化上保守的 AAA ATP 酶，对于细胞稳态至关重要。 VCP 与不同组的辅因子配合，通过泛素蛋白酶体系统 (UPS) 或自噬/溶酶体途径参与多种细胞过程。 NTD 结构域和 D1 ATP 酶结构域之间的界面经常发现的致病突变已被证明会导致 VCP 功能障碍，导致退行性疾病，包括与佩吉特骨病和额颞叶痴呆 (IBMPFD) 相关的包涵体肌病、肌萎缩侧索硬化症 (IBMPFD)。 ALS）和癌症。因此，VCP被认为是神经退行性疾病和癌症的潜在治疗靶点。之前的大多数研究发现VCP主要以六聚体的形式存在和发挥作用，它从蛋白质复合物中展开并提取泛素化底物进行降解。然而，最近的研究描述了一种新的 VCP 十二聚体状态，并揭示了由 D2 结构域核苷酸占据介导的 VCP 寡聚体状态的控制机制。在此，我们总结了有关 VCP 寡聚化、调节以及 VCP 对细胞功能和致病进展的潜在影响的最新知识。© 2024。作者，获得 Springer Nature Switzerland AG 的独家许可。

Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.