USP18 Partial Deficiency Leads to Early-Onset Childhood Inflammation

Abstract

Type I interferonopathies are characterized by an overabundance of IFN-I, which cause a broad spectrum of clinical presentation. Ubiquitin Specific Peptidase 18 (USP18) plays an important role in regulating the interferon (IFN) response by dampening the IFN-I signaling pathway. Additionally, USP18 removes ISG15 from proteins, in a process termed de-ISGylation. Synergistically, ISG15 prevents proteasomal degradation of USP18. Autosomal-recessive USP18 deficiency results in severe systemic inflammation and neurological anomalies, which is fatal in the perinatal period, unless treated with a JAK-STAT inhibitor. In our study, we identified three patients with genetic variations in USP18, who exhibited a spectrum of clinical features, including intracranial calcifications, lung opacities, hepatosplenomegaly, developmental delay, and high levels of circulating IFN-I. We sought to understand the pathophysiology of these USP18 mutations and the mechanistic process by which they cause disease. Expression of USP18 mRNA and protein was retained in all four of the patient’s mutations. Additionally, in all four patient mutations, USP18 maintained catalytic competencyand was capable of de-ISGylation. USP18 mutations also retained stabilization by ISG15. However, all four USP18 variants demonstrated higher levels of phosphorylation of STAT1 and STAT2 as compared to WT USP18, indicating an inability to negatively regulate interferon signaling, an important function of USP18. Additionally, both patient-derived fibroblasts and fibroblasts transduced and stimulated with IFNα2b had persistence of interferon-stimulated genes as compared to WT fibroblasts after a 36-hour recovery period. In conclusion, partial USP18 deficiency leads to early-onset childhood inflammation through an inability to control IFN-I signaling.