Hotchkiss Brain Institute, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
Alberta Child Health Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
Int J Mol Sci. 2024 May 22;25(11):5633. doi: 10.3390/ijms25115633.
In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM- and ATR-mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons, sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict.
在这篇综述中，我们研究了与各种细胞活动相关的功能多样的 ATP 酶（AAA-ATPase），即包含缬氨酸的蛋白（VCP/p97），及其分子功能、VCP 的突变景观以及 VCP 疾病的表型表现。VCP 对多种细胞功能至关重要，包括蛋白质质量控制、内质网相关降解（ERAD）、自噬、线粒体自噬、溶酶体自噬、应激颗粒形成和清除、DNA 复制和有丝分裂、DNA 损伤反应，包括核苷酸切除修复、ATM 和 ATR 介导的损伤反应、同源修复和非同源末端连接。VCP 变体引起多系统蛋白病，病理学可能发生在多种组织类型中，如骨骼肌、骨骼、大脑、运动神经元、感觉神经元，可能还有心肌，疾病进程难以预测。
