ISG15: leading a double life as a secreted molecule

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)-γ production. However, the mechanism by which ISG15 stimulates these cells also remains unclear. ISG15 and IFN-γ 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-γ 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. ISG15, a protein previously implicated in protection against viruses in mice, is now emerging as an important defense against mycobacteria in humans. In a review article, Dusan Bogunovic and his colleagues discuss recent research - much of it stemming from the scientists' own laboratory at The Rockefeller University, USA - showing that ISG15 is released by the immune system in response to mycobacterial species. Secretion of ISG15 in turn induces specialized immune cells known as lymphocytes to produce interferon-gamma, an immune-activating molecule that is essential for fighting mycobacterial infections, such as tuberculosis. People with mutations in the gene encoding ISG15 express low levels of interferon-gamma in their white blood cells and are highly prone to infection from otherwise poorly pathogenic mycobacterial bugs. The authors raise the possibility of modulating ISG15 levels as a way to combat infectious and inflammatory diseases.