ISG15 deficiency and increased viral resistance in humans but not mice

Scott D. Speer, et al.

Nature Communications. 2016 May 19. doi: 10.1038/ncomms11496

Speaker: Tan Sia Seng (陳聲昇)                                           Time: 15:00-16:00, Nov. 2, 2016

Commentator: Shun-Hua Chen, Ph.D. (陳舜華老師)          Place: Room 601

Abstract:

Interferon-stimulated gene 15 (ISG15) is an interferon (IFN)-α/β-inducible ubiquitin like protein. ISG15 exists in two distinct states: free molecule or conjugated to target protein lysine residues (ISGylation) that involves a conjugation pathway including E1, E2 and E3 enzymes [1]. In addition, de-ISGylation, a reverse action of ISGylation, is controlled by isopeptidase ubiquitin-specific protease 18 (USP18 or UBP43) [2]. The counter part of human ISG15 in mice is Isg15 that has antiviral immunity in response to viral infection, while human ISG15 has immune functions, buthas not had antiviral immunity. This paper is to clarify the discrepancy role of ISG15 between mice and human. The authors found that ISG expression exhibited and prolonged for few days when ISG15-deficient human cells (hTert immortalize fibroblast) is primed with IFNα/β. At the mean times, several viruses from multiple families are significantly inhibited compare to control groups. Hence, the authors conclude that ISG15-deficient IFN-primed cells are resistant to viral infection. Further confirmation, the ISG response and virus replication are rescued by restoring WT ISG15 and ISG15ΔGG (conjugation-deficient mutant) in ISG15-deficient fibroblasts. Moreover, the authors were unable to reproduce these results in mice studies with multiple virus infection since there are no differences in ISG response compared between Isg15-deficient cell and wild type controlcells, either primed or no primed with IFN. In addition, gain of function or loss of function assays results demonstrated that the levels of Usp18 do not response to Isg15. These data confirm that the impact of ISG15 by IFN-α/β-signaling may indeed differ between human and mice. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency can be explained by the requirement of ISG15 to sustain USP18 levels in humans, but the mechanism does not operate in mice. 

References

1.        Morales, D.J. and D.J. Lenschow, The antiviral activities of ISG15. J Mol Biol, 2013. 425(24): p. 4995-5008.

2.         Zhang, D. and D.E. Zhang, Interferon-stimulated gene 15 and the protein ISGylation system. J Interferon Cytokine Res, 2011. 31(1): p. 119-30.