The binding of ISG15 to NEDD4-1, NEDL1, NEDL2, or WWP2 can block their interaction with ubiquitin-E2 enzymes and interfere with the ubiquitination of retroviral group-specific antigen precursors and matrix proteins, such as VP40 of Ebola with a PPxY motif, which is essential for the release/budding of Ebola, vesicular stomatitis, and rabies virus particles [247,248]. Here, HECW1 is linked to Ebola hemorrhagic fever.