(A) Desensitization assay (immunoblot, fibroblasts) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed, n=4, ANOVA with Sidak’s post-test). (C) Schematic of USP18 mechanism of action and proposed model of STAT2R148W pathomechanism. (D) Modelling of exposed WT (R148)/mutant (W148) residue, demonstrating charge-change (blue = positive, red = negative) and possible steric restriction. (E) Co-immunoprecipitation of USP18 by STAT2 in U6A cells expressing STAT2WT or STAT2R148W with (F) densitometry analysis (USP18/STAT2, ratio to WT, one-sample t test). Data are mean ± SEM (** P<0.01, **** <0.0001).