Interferon-Stimulated Gene 15 in the Control of Cellular Responses to Genotoxic Stress

Jeon, Young Joo; Park, Jong Ho; Chung, Chin Ha

The product of interferon (IFN)-stimulated gene 15 (ISG15) is the first reported UBL (Haas et al., 1987) . This 15-kDa protein consists of two ubiquitin-like domains corresponding to the N-and C-terminal regions, which share 29% and 31% amino acid sequence identities with ubiquitin, respectively (Haas et al., 1987; Jeon et al., 2010) . Like ubiquitination, ISG15 is conjugated to target proteins by an enzymatic cascade: ISG15-activating E1 enzyme (UBE1L), ISG15-conjugating E2 enzyme (UBCH8), and ISG15 E3 ligases (e.g., HERC5 and EFP) (Kim et al., 2004; Wong et al., 2006; Yuan and Krug, 2001; Zhao et al., 2004; Zou and Zhang, 2006) . This conjugation process can be reversed by the major deISGylating enzyme UBP43, also called USP18 . ISG15 is not present in Drosophila, Caenorhabditis, and Saccharomyces, indicating that its functions are restricted to higher animals. ISG15 is robustly induced by type-I IFNs, lipopolysaccharide, and viral infection (Farrell et al., 1979; Kim et al., 2002; Loeb and Haas, 1992; Malakhova et al., 2002) . One of the major components of the innate immune response is the activation of type I IFN signaling pathways (Platanias, 2005; Taniguchi and Takaoka, 2001) . Proteomic analysis has revealed that regulatory proteins involved in antiviral IFN signaling pathways, such as RIG-I, IRF3, MDA-5, STAT1, JAK1, and filamin B, serve as targets for ISG15 modification (Arimoto et al., 2008; Jeon et al., 2009; Kim et al., 2008; Zhao et al., 2005) . Moreover, ISG15 and its conjugation to target proteins have been implicated in impairment of viral replication in vivo (Lu et al., 2006; Malakhova and Zhang, 2008; Okumura et al., 2008) . Conversely, certain viruses induce their own proteins that can block the expression of ISG15 (e.g., NS3/4A) or generation of ISG15-conjugated proteins (e.g., NS1B) or promote deconjugation of ISG15 from its target proteins (i.e., deISGylating enzymes, including OTU, PLpro, and viral E3 protein), thus abrogating the antiviral immune responses Lindner et al., 2005; Loo et al., 2006; Ratia et al., 2008; Yuan and Krug, 2001; Zhao et al., 2016) . In addition, mice lacking ISG15 or UBE1L exhibit increased susceptibility to infection by certain viruses, including influenza B virus, herpes simplex virus, and/or Sindbis virus (Giannakopoulos et al., 2009; Lai et al., 2009; , further indicating the role of ISG15 and its conjugation of target proteins in antiviral responses.