The enzymes of the ISGylation pathway play a pivotal role in the innate immune response. Three classes of enzymes are involved in the process of ISGylation; the Interferon-stimulated 15 kDa protein (ISG15) activating enzyme UBA7 (E1), the ISG15 conjugating enzyme UBE2L6 (E2) and the ubiquitin like modifier ISG15. ISG15 is a member of the ubiquitin like modifiers and the human gene was first described by Zhao et al. (2004). ISG15 functions in various biological pathways from pregnancy to innate immune responses (Ritchie and Zhang. 2004; Zhao et al., 2004). Secretion of ISG15 from monocytes in response to type I Interferons has been shown to cause natural killer (NK) cell proliferation and an increase in non-(major histocompatibility complex) MHC cytotoxicity (Meraro et al., 2002). ISG15 has also been shown to function intracellularly, being covalently conjugated to other proteins by UBA7, UBE2L6 and E3 ligases via a multistep process analogous to ubiquitylation (Loeb and Haas. 1992; Zhao et al., 2005). Ubiquitin-Specific Protease, 43kDa (UBP43) also known as Ubiquitin-Specific Protease, 18 (USP18) has been shown to specifically remove ISG15 from modified proteins (Malakhov et al., 2002).
Loeb KR, Haas AL (1992) The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem 267, 7806-13.
Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE (2002) UBP43 (USP18) specifically removes ISG15 from conjugated proteins. J Biol Chem 277, 9976-81.
Meraro D, Gleit-Kielmanowicz M, Hauser H, Levi BZ (2002) IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: characterization of a new subtype of IFN-stimulated response element. J Immunol 168, 6224-31.
Ritchie KJ, Zhang DE (2004) ISG15: the immunological kin of ubiquitin. Semin Cell Dev Biol 15, 237-46.
Zhao C, Beaudenon SL, Kelley ML, Waddell MB, Yuan W, Schulman BA, Huibregtse JM, Krug RM (2004) The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein. Proc Natl Acad Sci USA 101, 7578-82.
Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM (2005) Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci USA 102, 10200-5.