Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy

Abstract

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing. Although the etiology of IBD is unknown, it is thought that genetically susceptible individuals display an inappropriate inflammatory response to commensal microbes, resulting in intestinal tissue damage. Key proteins involved in regulating the immune response, and thus in inflammation, are the small triphosphate-binding protein Rac and its regulatory network. Recent data suggest these proteins to be involved in (dys)regulation of the characteristic inflammatory processes in IBD. Moreover, Rac-gene variants have been identified as susceptibility risk factors for IBD, and Rac1 GTPase signaling has been shown to be strongly suppressed in non-inflamed mucosa compared with inflamed colonic mucosa in IBD. In addition, first-line immunosuppressive treatment for IBD includes thiopurine therapy, and its immunosuppressive effect is primarily ascribed to Rac1 suppression. In this review, we focus on Rac modification and its potential role in the development of IBD, Rac as the molecular therapeutic target in current thiopurine therapy, and the modulation of the Rac signal transduction pathway as a promising novel therapeutic strategy.

Fig. 1

Simplified scheme of the ‘role’ of Rac and the molecular switch of active Rac and inactive Rac, regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). Moreover, Rac GEF reaction may proceed by competitive displacement of bound GDP by GTP through a transient intermediate of GEF (GTP-Rac-GDP) [65]. GDP guanosine diphosphate, GTP guanosine triphosphate

Fig. 2

Model for thiopurine-mediated immunosuppression. The guanine nucleotide exchange factor (GEF) Vav1 activates Rac1 by the exchange of GDP for GTP. The active thiopurine metabolite thio-GTP binds to Rac1 instead of GTP. This thio-GTP-bound Rac 1 (Rac1thio-GTP) induces T-cell apoptosis (by a decrease of Bcl-XL [anti-apoptotic signal]) via inhibition of Rac 1 activation in T cells. Active Rac1 also ensures de-phosphorylation of Ezrin–Radixin–Moesin (pERM) to ERM. GDP guanosine diphosphate, GTP guanosine triphosphate