HERC5 (HECT and RLD domain-containing E3 ubiquitin ligase 5) is constitutively expressed at low or undetectable levels in most normal adult tissues and in a subset of cancer cell lines. It is an evolutionarily ancient restriction factor that inhibits the replication of diverse viruses. By virtue of its C-terminal HECT domain, HERC5 is the main cellular E3 ligase for conjugating ISG15 to substrates and localizes to polyribosomes to modify newly translated viral proteins, thereby disrupting key aspects of viral particle production. E3 ligase-independent antiviral activity has also been demonstrated towards HIV-1, where it inhibits the nuclear export of incompletely-spliced viral RNAs by a mechanism requiring its N-terminal RCC1-like domain (RLD). (PMID: 34572049)