(A) VCP is hijacked by flaviviruses to disassemble stress granules to free the viral replication machinery through a direct interaction between the NPL4 adaptor and viral protein, NS4B. VCP–UBXD8 also regulates stress granule disassembly at the ER. (B) The interaction between VCP and ataxin-3 stimulates the deubiquitylation of the Ptdlns3K complex component Beclin1, stabilizing the complex and initiating phagophore formation. (C) The VCP–UBXD8 complex regulates ER-mitochondria contact sites by maintaining SCD1 protein levels and thereby membrane lipid saturation and composition. VCP an also directly modulate tethering proteins. (D) VCP plays multiple roles in several steps of autophagy. VCP–U–N plays a role in autophagosome-lysosome fusion, and VCP–UBXD1 functions in the clearance of damaged lysosomes (lysophagy). The VCP–SVIP complex maintains the integrity of the tubular lysosome network.