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Description

Transitional endoplasmic reticulum ATPase (UniProt:P55072, also known as EC:3.6.4.6, TER ATPase, 15S Mg(2+)-ATPase p97 subunit, Valosin-containing protein, VCP) is encoded by the VCP gene (Gene ID: 7415) in human. VCP is a homohexameric protein that forms a ring-shaped particle and displays a six-fold radial symmetry. It is shown to be essential for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. It is involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles, which derive from part-rough, part-smooth transitional elements of tER. Vesicle budding from the tER is reported to be an ATP-dependent process. It is shown that the ternary complex containing UFD1, VCP and NPLOC4 regulates spindle disassembly at the end of mitosis. This complex binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. VCP is also involved in DNA damage response. It is recruited to double-strand breaks sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. It is recruited to stalled replication forks by DNA-binding metalloprotease SPRTN and together they are involved in the repair of covalent DNA-protein cross-links during DNA synthesis. VCP is also required for cytoplasmic retro-translocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. DNA damage is reported to induce phosphorylation of serine 784 that selectively enhances chromatin-associated protein degradation and is required for DNA repair, signaling, and cell survival. These functional effects of serine 784 phosphorylation correlate with a decrease in VCP association with chromatin, cofactors NPL4/UFD1, and polyubiquitinated substrates. (Ref.: (Ref.: Zhu, C., et al.(2020). Cell Rep. 31(10), 107745, Fielden, J., et al. (2020). Nat. Commun. 11(1), 1274).