ISG15 and ISGylation Regulate the Host Response to Viral Infections

During viral infection, the host innate immune response provides early protection. To control virus spread, the host cells produce type I interferons (IFNs) as first line of defense, acting as antiviral and inflammatory cytokines. Type I IFNs binding with interferon α/β receptor (IFNAR) triggers the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway to induce the synthesis of a few hundred IFN-stimulated genes (ISGs) which inhibit virus replication at different steps of the virus replication cycle [1]. Ubiquitin-like protein ISG15 is one of the most strongly and promptly induced ISG following virus infection, and many studies have demonstrated that ISG15 can directly inhibit viral replication and modulate host immune response. ISG15 is one of the members of ubiquitin families, which include ubiquitin and ubiquitin-like modifiers (Ubls). ISG15 can covalently conjugate to target proteins via isopeptide bonds and this conjugation process of protein modification is known as ISGylation which is involved in the regulation of many cellular processes. To date, proteomic studies have identified a few hundred ISG15 target proteins [2,3]. Research of specific ISG15 targeted proteins have found that through competing with ubiquitin binding sites, ISG15 can inhibit protein ubiquitination, indirectly regulating protein degradation [4].