Human intracellular ISG15 prevents interferon-?/? over-amplification and auto-inflammation.

ABSTRACT: Intracellular ISG15 is an interferon (IFN)-?/?-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-?/?-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency 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-?-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-?/? immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutières syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-?/? signalling, resulting in the enhancement and amplification of IFN-?/? responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-?/? immunity. In humans, intracellular ISG15 is IFN-?/?-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-?/? and prevention of IFN-?/?-dependent autoinflammation.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC4303590 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature