Interferon-stimulated Gene 15 (ISG15) Activating Enzyme (E1), also known as ubiquitin-activating enzyme1-like (UBE1L), UBA7, and UBE2, is a 1012 amino acid (aa) member of the ubiquitin-activating enzyme family with a predicted molecular weight of 111 kDa. The mouse and rat ISG15 E1/UBE1L orthologs share 80% aa sequence identity with the human protein. ISG15 E1/UBE1L catalyzes the activation of the C-terminal carboxyl group of the small ubiquitin-like modifier ISG15. Like other E1 enzymes, ISG15 E1/UBE1L contains a conserved ATP-binding domain and an active site cysteine residue, Cys599 in humans. It is expressed in multiple tissues in response to IFN-alpha or -beta, but the covalent attachment of ISG15 to protein substrates (ISGylation) is not required for IFN-alpha or -beta signaling. In addition, ISG15 E1/UBE1L knockout mice appear to have normal embryonic development and fertility. However, it has been suggested that ISG15 E1/UBE1L may play a role in viral immunity as these knockout mice demonstrate increased susceptibility to influenza infection. ISG15 E1/UBE1L has also been shown to modulate erythroid differentiation and mediate retinoid-induced differentiation of acute promyelocytic leukemia cells. ISG15 E1/UBEL1 is downregulated in lung cancer and has been shown to downregulate Cyclin D in lung cancer cells.