Involvement of proteasomes in gene induction by interferon and double-stranded RNA

Cytokine induced gene expression is mediated through the ligand-dependent a ctivation of the janus kinase (jak)/signal transducer and activator of tran scription (STAT) signal transduction pathway, The ubiquitin proteasome path way functions in the controlled degradation of cellular proteins, and regul ates cytokine signal transduction through the degradation of specific signa ling components. Interferon (IFN) treatment induces genes that function in ubiquitin conjugation, suggesting a reciprocal regulation of proteasome act ivity and IFN action; however, a role for the proteasome in IFN-alpha -indu ced gene expression has not been examined, In this report, we find that pro teasome inhibitors markedly reduce the induction of interferon-stimulated-g ene 15 (ISG15), ISG43, and STAT1 by IFN-alpha and double-stranded RNA (dsRN A), The reduction in gene expression by proteasome inhibitors was dose-depe ndent, and was specific for ISGs, Neither STAT1 phosphorylation nor ISGF3 a ctivation was affected by proteasome inhibition at early times post-IFN tre atment. Cycloheximide treatment diminished the effect of proteasome inhibit ors on ISG induction, implicating an IFN/dsRNA-induced protein in this acti vity, These findings demonstrate that a functional proteasome is required f or optimal ISG induction, and are consistent with a model in which IFN and dsRNA induce a proteasome-sensitive repressor of ISG expression. (C) 2001 A cademic Press.