Exp Mol Med.  2013 Apr;45(4):e18.

ISG15: leading a double life as a secreted molecule

• Bogunovic
• Boisson-Dupuis S
• Casanova J

Abstract

ISG15 is a well-known intracellular ubiquitin-like molecule involved in ISGylation. However, a recent study has revived the notion first put forward two decades ago that ISG15 is also a secreted molecule. Human neutrophils, monocytes and lymphocytes can release ISG15, even though this protein has no detectable signal peptide sequence. ISG15 has also been found in the secretory granules of granulocytes. The mechanism underlying ISG15 secretion is unknown. Secreted ISG15 acts on at least T and natural killer (NK) lymphocytes, in which it induces interferon (IFN)-gamma production. However, the mechanism by which ISG15 stimulates these cells also remains unclear. ISG15 and IFN-gamma seem to define an innate circuit that operates preferentially, but not exclusively, between granulocytes and NK cells. Inherited ISG15 deficiency is associated with severe mycobacterial disease in both mice and humans. This infectious phenotype probably results from the lack of secreted ISG15, because patients and mice with other inborn errors of IFN-gamma immunity also display mycobacterial diseases. In addition to raising mechanistic issues, the studies described here pave the way for clinical studies of various aspects, ranging from the use of recombinant ISG15 in patients with infectious diseases to the use of ISG15-blocking agents in patients with inflammatory diseases.

Keyword

ISG15; MSMD; mycobacteria; secreted molecule

MeSH Terms

Amino Acid Sequence
Animals
Cytokines/chemistry/*secretion
Humans
Interferon-gamma/secretion
Metabolism, Inborn Errors/metabolism
Models, Biological
Molecular Sequence Data
Cytokines
Interferon-gamma