ISG15: leading a double life as a secreted molecule - PubMed (original) (raw)

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ISG15: leading a double life as a secreted molecule

Dusan Bogunovic et al. Exp Mol Med. 2013.

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)-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.

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Figures

Figure 1

Figure 1

Tertiary structures of ISG15 and ubiquitin, alone and in combination. The structural information was obtained from the protein data bank (PDB): ubiquitin (PDB code: 1UBQ) and ISG15 (PDB code: 1Z2M). The images were obtained with PyMol software (a). Amino-acid sequence similarity analysis was performed with ISG15 molecules of human, bovine and zebrafish origin, and on ubiquitin of human, bovine, zebrafish and yeast origin. Conservation was scored with PRALINE, which assigns a score from 0, for the least conserved alignment position, to 10, for the most conserved alignment position (b).

Figure 2

Figure 2

Inborn errors of the interleukin (IL)-12-interferon (IFN)-γ circuit in patients with Mendelian susceptibility to mycobacterial diseases (MSMDs). Proteins for which mutations in the corresponding genes have been associated with MSMD are shown in blue. MSMD-causing mutations of IL12B, IL12RB1 and ISG15 impair the production of IFN-γ. MSMD-causing mutations of IFNGR1, IFNGR2 and STAT1 impair the cellular response to IFN-γ. MSMD-causing mutations of NEMO impair the T-cell response and CD40-dependent production of IL-12. MSMD-causing mutations of IRF8 result in a loss of myeloid dendritic cells, and mutations of CYBB result in oxidative burst defects in macrophages.

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