Abstract
Valosin-containing protein (VCP), an AAA (ATPase associated with diverse cellular activities) ATPase, has been reported to participate in various biological events, including ubiquitin-dependent protein degradation, organelle biogenesis, DNA damage response, and cell cycle regulation. Studies of familial inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) have linked this disease to VCP mutations. We established a Drosophila IBMPFD model by tissue-specific expression of TER94 (Drosophila VCP homolog) mutants that correspond to VCP disease alleles, and by which to demonstrate that our model could recapitulate the multi-system disorders characteristic of IBMPFD. Furthermore, we provided evidence showing that IBMPFD-causing mutants are dominant-active alleles and may cause an imbalance of cellular ATP, which in turn perturb ATP-dependent processes within cells and progressively lead to the degeneration of tissues that demand higher energy expenditure. Apart from revealing the underlying mechanism of IBMPFD pathogenesis, we identified a potential role of TER94 in maintaining post-mitotic nuclear structure. It is already known that VCP is involved in nuclear envelope reformation after mitosis; however, we observed the size of the nuclei remarkably increased in non-dividing cells expressing TER94 dominant-negative mutants. Relationship between the nuclear morphology and cellular localization of TER94 illustrated that the activity of TER94 hexamer in the nucleus is required for maintaining a normal nuclear size. In addition, we found that ubiquitinated proteins accumulated and were associated with TER94 in the nucleus as the function of TER94 being disrupted, suggesting that TER94 might have a role in nuclear protein quality control and the nuclear enlargement could be attributed to aberrant nuclear protein degradation. Interestingly, the nuclear expansion induced by dominant-negative mutant TER94 were accompanied with altered chromatin distribution and histone modification, implicating that the gene expression profile could be affected due to the change in nuclear morphology. This also indicates that the maintenance of nuclear structure is important for the nucleus to function properly.