Humans deficient in USP18 or ISG15 develop severe autoimmune disease due to uncontrolled IFN-I signaling (Zhang et al., 2015; Meuwissen et al., 2016; Bogunovic et al., 2012; Martin-Fernandez et al., 2020; Malakhova et al., 2006). The gene discussed is USP18; the disease is autoimmune disease.