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Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.

IFN-alpha/beta plays an essential role in innate immunity against viral and bacterial infection. Among the proteins induced by IFN-alpha/beta are the ubiquitin-like ISG15 protein and its E1- (Ube1L) and E2- (UbcH8) conjugating enzymes, leading to the conjugation of ISG15 to cellular proteins. It is likely that ISG15 conjugation plays an important role in antiviral response because a human virus, influenza B virus, inhibits ISG15 conjugation. However, the biological function of ISG15 modification remains unknown, largely because only a few human ISG15 target proteins have been identified. Here we purify ISG15-modified proteins from IFN-beta-treated human (HeLa) cells by using double-affinity selection and use mass spectroscopy to identify a large number (158) of ISG15 target proteins. Eight of these proteins were subjected to further analysis and verified to be ISG15 modified in IFN-beta-treated cells, increasing the likelihood that most, if not all, targets identified by mass spectroscopy are bona fide ISG15 targets. Several of the targets are IFN-alpha/beta-induced antiviral proteins, including PKR, MxA, HuP56, and RIG-I, providing a rationale for the inhibition of ISG15 conjugation by influenza B virus. Most targets are constitutively expressed proteins that function in diverse cellular pathways, including RNA splicing, chromatin remodeling/polymerase II transcription, cytoskeleton organization and regulation, stress responses, and translation. These results indicate that ISG15 conjugation impacts nuclear as well as cytoplasmic functions. By targeting a wide array of constitutively expressed proteins, ISG15 conjugation greatly extends the repertoire of cellular functions that are affected by IFN-alpha/beta.

Pubmed ID: 16009940


  • Zhao C
  • Denison C
  • Huibregtse JM
  • Gygi S
  • Krug RM


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 19, 2005

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI11772
  • Agency: NCI NIH HHS, Id: CA72943
  • Agency: NIGMS NIH HHS, Id: GM67945
  • Agency: NHGRI NIH HHS, Id: HG00041

Mesh Terms

  • Antiviral Agents
  • Cytokines
  • DEAD-box RNA Helicases
  • GTP-Binding Proteins
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • Influenza B virus
  • Interferon Type I
  • Mass Spectrometry
  • Myxovirus Resistance Proteins
  • RNA Helicases
  • Ubiquitin-Activating Enzymes
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitins
  • eIF-2 Kinase