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© Research
Project

ISG15 contribution to tuning of IFN-I activity and interferonopathies

Scientific Fields
Diseases
Organisms
Applications
Technique
Starting Date
15
Sep 2015
Status
Ongoing
Members
1
Structures
1
Publications
1

About

We have reported on the implication of the ubiquitin-like ISG15 protein in the negative regulation of IFN-I response in humans. ISGylation is a major post-translational modification whereby numerous proteins are conjugated to ISG15, with consequences that are largely protein-specific. The ISGylation process requires a set of enzymes that are transcriptionally co-induced by IFN with ISG15. USP18 cleaves ISG15 from conjugates and thus counterbalances ISGylation. We have analyzed the interplay between USP18 and ISG15 in human cells and in particular the role of ISG15 in the USP18-mediated attenuation of type I IFN response. In collaboration with an international team of geneticists and clinicians, we studied patients with complete ISG15 deficiency. These rare patients develop an auto-inflammatory pathology, characterized by brain calcifications and an IFN-I signature in blood cells, reminiscent of other genetic disorders known as interferonopathies. Through the analysis of IFN signaling in patients’ fibroblasts, we found that ISG15 takes part in the regulatory loop that attenuates IFN response. ISG15 does so by stabilizing USP18, the bona fide negative regulator. Thus, ISG15 acts as the regulator of the regulator to tune down IFN activities. Intriguingly, we have found that in mice Isg15 does not attenuate IFN signaling, which may account for the strikingly different phenotypes of ISG15 deficiency in humans and mice. Work in collaboration with D. Bogunovic (Icahn School of Medicine at Mount Sinai) is ongoing to understand the molecular basis of this species-specific divergence in the regulation of the IFN-I response.

Fundings

References