Intracellular ISG15 is an interferon (IFN)-Î±/Î²-inducible ubiquitinlike modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-Î±/Î²-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-Î³-inducing molecule. We show here that ISG15- deficient patients also displayunanticipated cellular, immunological and clinical signs of enhanced IFN-Î±/Î² immunity, reminiscent of the Mendelian autoinflammatory interferonopathiesAicardi-Goutieres syndrome andspondyloenchondrodysplasia.We further showthat an absence of intracellular ISG15 in the patients cells prevents the accumulation of USP18, a potent negative regulator of IFN-Î±/Î² signalling, resulting in the enhancement and amplification of IFNÎ±/Î² responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-Î±/Î² immunity. Inhumans, intracellular ISG15 is IFN-Î±/Î²-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-Î±/Î² and prevention of IFN-Î±/Î²-dependent autoinflammation.
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|Titolo:||Human intracellular ISG15 prevents interferon-Î±/Î² over-amplification and auto-inflammation|
|Data di pubblicazione:||2015|
|Appare nelle tipologie:||01.01 - Articolo su rivista|