Interferon-stimulated GTPases in autoimmune and inflammatory diseases: promising role for the guanylate-binding protein (GBP) family

Abstract

Human IFNs are secreted cytokines shown to stimulate the expression of over one thousand genes. These IFN-inducible genes primarily encode four major protein families, known as IFN-stimulated GTPases (ISGs), namely myxovirus-resistance proteins, guanylate-binding proteins (GBPs), p47 immunity-related GTPases and very large inducible guanosine triphosphate hydrolases (GTPases). These families respond specifically to type I or II IFNs and are well reported in coordinating immunity against some well known as well as newly discovered viral, bacterial and parasitic infections. A growing body of evidence highlights the potential contributory and regulatory roles of ISGs in dysregulated inflammation and autoimmune diseases. Our focus was to draw attention to studies that demonstrate increased expression of ISGs in the serum and affected tissues of patients with RA, SS, lupus, IBD and psoriasis. In this review, we analysed emerging literature describing the potential roles of ISGs, particularly the GBP family, in the context of autoimmunity. We also highlighted the promise and implications for therapeutically targeting IFNs and GBPs in the treatment of rheumatic diseases.

Keywords: GBP; IBD; ISG; Sjögren's syndrome; autoimmune; interferons; lupus; psoriasis; rheumatoid arthritis.

Fig. 1

The signalling pathways affected by guanylate-binding proteins in response to stimulation Activated signal transducers and activators of transcription (STATs) translocate to the nucleus and bind to the IFN-stimulated response elements (ISREs) (for Type 1 IFN) and gamma-activated sequence sites (GASs) (for Type 2 IFN) promoter region to induce the transcription of IFN-stimulated (guanosine triphosphate hydrolases (GTPases)) (ISGs). Induction of guanylate-binding proteins (GBPs), one of the IFN-induced GTPases, further influences various signalling pathways. Studies suggested that GBP1 and GBP5 cause activation of the NF-κB signalling pathway. mGBP2 causes the suppression of NF-κB and Wnt signalling [47–50].