R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity

Abstract

G protein-coupled receptors (GPCRs) have important functions in both innate and adaptive immunity, with the capacity to bridge interactions between the two arms of the host responses to pathogens through direct recognition of secreted microbial products or the by-products of host cells damaged by pathogen exposure. In the mid-1990s, a large group of intracellular proteins was discovered, the regulator of G protein signaling (RGS) family, whose main, but not exclusive, function appears to be to constrain the intensity and duration of GPCR signaling. The R4/B subfamily--the focus of this review--includes RGS1-5, 8, 13, 16, 18, and 21, which are the smallest RGS proteins in size, with the exception of RGS3. Prominent roles in the trafficking of B and T lymphocytes and macrophages have been described for RGS1, RGS13, and RGS16, while RGS18 appears to control platelet and osteoclast functions. Additional G protein independent functions of RGS13 have been uncovered in gene expression in B lymphocytes and mast cell-mediated allergic reactions. In this review, we discuss potential physiological roles of this RGS protein subfamily, primarily in leukocytes having central roles in immune and inflammatory responses. We also discuss approaches to target RGS proteins therapeutically, which represents a virtually untapped strategy to combat exaggerated immune responses leading to inflammation.

Keywords: G proteins; RGS proteins; immune system; inflammation.

Fig. 1

Proteins containing a regulator of G protein signaling (RGS) domain. The various RGS subfamilies, together with their known members and distinguishing domain structures, are shown. Additional proteins containing RGS homology domains (lower right) are also included but are not discussed in this review. Abbreviations: PDZ post synaptic density protein (PSD95), Drosophila disk large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) [PDZ] domain, DEP Disheveled, Egl-10 and Pleckstrin domain, PTB protein tyrosine binding domain, RBD Ras binding domain, GGL Gγ-like domain