Beyond ISGlylation: Functions of Free Intracellular and Extracellular ISG15

J Interferon Cytokine Res. 2017 Jun;37(6):246-253. doi: 10.1089/jir.2016.0103. Epub 2017 May 3.

Abstract

ISG15 is a ubiquitin-like type I IFN-stimulated protein of 15 kDa and is one of the most prominently expressed proteins in viral infections. ISG15 is widely known to be involved in a process called ISGylation, where it binds to over 150 targets from a variety of classes of proteins including central immune signaling pathways such as those mediated by NFκB, JNK, and IRF-3. However, ISG15 also exists in a free form that can act intra- or extracellularly. In vitro and in vivo evidences suggest that free ISG15 play different roles in several cellular processes, from cancer and defense against viral infections to activation of immune cells such as lymphocytes, monocytes, and NK cells. This review discusses the roles of free intracellular and secreted ISG15 approaching questions yet to be answered about the mechanism of action of this protein.

Keywords: ISG15; ISGylation; immunomodulation.

Publication types

  • Review

MeSH terms

  • Bacterial Infections / genetics
  • Bacterial Infections / immunology*
  • Bacterial Infections / microbiology
  • Cytokines / genetics
  • Cytokines / immunology*
  • Gene Expression Regulation
  • Humans
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Monocytes / immunology
  • Monocytes / microbiology
  • Monocytes / virology
  • Neutrophils / immunology
  • Neutrophils / microbiology
  • Neutrophils / virology
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / microbiology
  • T-Lymphocytes / virology
  • Ubiquitins / genetics
  • Ubiquitins / immunology*
  • Virus Diseases / genetics
  • Virus Diseases / immunology*
  • Virus Diseases / virology
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology

Substances

  • Cytokines
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Ubiquitins
  • ISG15 protein, human
  • Interferon-gamma
  • eIF-2 Kinase