Competitive inhibition of translation initiation by ISGylated 4EHP ISGylation of protein translation regulator 4EHP Monoubiquitination of N-myristoyl GAG (P12493) protein ISGylation of host protein filamin B ISGylation of protein phosphatase 1 beta (PP2CB) ISGylation of E2 conjugating enzymes Interaction of ISG15 with NEDD4 and inhibition of Ebola virus budding ISGylation of viral protein NS1 Translocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleus ISGylation of IRF3 ISGylation of host proteins Interaction of E3 ligase with ISG15:E2 complex Transfer of ISG15 from E1 to E2 (UBCH8) Activation of ISG15 by UBE1L E1 ligase Regulation of protein ISGylation by ISG15 deconjugating enzyme USP18 PIN1 mediated IRF3 degradation PathwayStep6954 PathwayStep7085 PathwayStep7084 PathwayStep7087 PathwayStep7086 PathwayStep7081 PathwayStep7080 PathwayStep7083 PathwayStep7082 PathwayStep7089 PathwayStep7088 PathwayStep7094 PathwayStep7093 PathwayStep7092 PathwayStep7091 PathwayStep7090 ISG15 antiviral mechanism Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell. Pubmed12582176 Pubmed15970528 Pubmed16009940 Pubmed20153823 Pubmed20946978 Reactome Database ID Release 431169408 Reactome, http://www.reactome.org ReactomeREACT_115831 Reviewed: Zhang, DE, 2011--0-2-