Nucleocytoplasmic shuttling of valosin-containing protein (VCP/p97) regulated by its N domain and C-terminal region

• IBMPFD mutations decrease the nuclear distribution of VCP.
• The peptide G780AGPSQ of VCP regulates its retention in the nucleus and nucleoli.
• C-terminal region deletion elevates the nuclear retention of VCP IBMPFD mutants.

Valosin-containing protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G780AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP proteins.