ISG15 Deficiency: An expanding phenotype

ISG15 is a Type I IFN-inducible intracellular protein that interacts with and stabilizes USP18, a negative regulator of IFN-I pathway, and thus acts in a negative feedback loop. Lung damage caused by pulmonary fibrosis cannot be repaired, and can require lung transplantation; therefore, a better understanding of the causes is crucial. Here, we describe the case of a 13-year-old female presented with interstitial lung disease due to a mutation in ISG15. There is an increasing number of ISG15 deficient patients who present with lung fibrosis, but the significance of ISG15 in proper wound healing and fibrosis is unknown. We aim to investigate ISG15’s role in fibrosis by studying this mutant. Whole exome sequencing and molecular cloning was performed to identify the mutation and its expressivity. INFα stimulation of cells carrying the mutation to assess differential levels of apoptosis, necroptosis and pyroptosis compared to WT cells. Scratch wound assay to assess the mutant’s ability to effectively heal a wound. Fibrosis due to the overactivation of fibroblasts to myofibroblasts due to TGFβ and IFNα exposure. The mutation is a duplication of a cysteine at position 463 of ISG15, causing a frameshift mutation at the very end of the gene which generates an mRNA transcript without a stop codon. Further analysis revealed that even though the mutant ISG15 mRNA gets transcribed, it does not get translated (ISG15 deficiency). In-vitro experiments revealed no changed in apoptosis, necroptosis nor pyroptosis when mutant cells were treated with IFNα, but they were more sensitive to the antiproliferation effects of IFNα. Therefore, these data suggest a possible mechanism by which ISG15 deficiency could aid to lung fibrosis due to the inability of the fibroblasts to properly proliferate and heal a wound.