The antiviral activities of ISG15

J Mol Biol. 2013 Dec 13;425(24):4995-5008. doi: 10.1016/j.jmb.2013.09.041. Epub 2013 Oct 3.


Post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. Ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. Interferon stimulated gene 15 (ISG15) is a ubiquitin-like modifier induced by type I interferon. In addition to conjugating to potentially hundreds of target proteins, ISG15 can be found in an unconjugated form both inside of the cell and released from interferon stimulated cells into the extracellular environment. Due to its robust expression after type I interferon stimulation and the broad panel of proteins that it targets, ISG15 has drawn much attention as a potential regulator of the immune response and has been shown to mediate protection in a number of different viral infection models. Here we will review the current state of the field of ISG15, the viruses against which ISG15 mediates protection, and the mechanisms by which ISG15 exerts antiviral activity.

Keywords: ASLV; CHIKV; Chikungunya virus; ESCRT; HIV-1; HPV; HSV-1; IRF3; ISG15; JNK; Jun N-terminal kinase; LCMV; MEF; NDV; NK; Newcastle disease virus; PKR; RIG-I; SeV; Sendai virus; VLP; VSV; WNV; WT; West Nile virus; avian sarcoma leukosis virus; endosomal sorting complexes required for transport; herpes simplex virus 1; human immunodeficiency virus 1; human papilloma virus; innate immunity; interferon regulatory factor 3; interferon stimulated gene 15; interferons; lymphocytic choriomeningitis virus; mouse embryonic fibroblast; natural killer; protein kinase R; retinoic acid inducible gene 1; short interfering RNA; siRNA; ubiquitin-like protein; vesicular stomatitis virus; virus-like particle; viruses; wild type.

Publication types

  • Review

MeSH terms

  • Antiviral Agents / immunology*
  • Antiviral Agents / metabolism
  • Cytokines / genetics
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Humans
  • Immunity, Innate*
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Protein Processing, Post-Translational*
  • Ubiquitins / genetics
  • Ubiquitins / immunology*
  • Ubiquitins / metabolism
  • Virus Release / immunology
  • Virus Replication / immunology


  • Antiviral Agents
  • Cytokines
  • Interferon Type I
  • Ubiquitins
  • ISG15 protein, human