Implications of non-canonical G-protein signaling for the immune system

Abstract

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which consist of three subunits α, β, and γ, function as molecular switches to control downstream effector molecules activated by G protein-coupled receptors (GPCRs). The GTP/GDP binding status of Gα transmits information about the ligand binding state of the GPCR to intended signal transduction pathways. In immune cells heterotrimeric G proteins impact signal transduction pathways that directly, or indirectly, regulate cell migration, activation, survival, proliferation, and differentiation. The cells of the innate and adaptive immune system abundantly express chemoattractant receptors and lesser amounts of many other types of GPCRs. But heterotrimeric G-proteins not only function in classical GPCR signaling, but also in non-canonical signaling. In these pathways the guanine exchange factor (GEF) exerted by a GPCR in the canonical pathway is replaced or supplemented by another protein such as Ric-8A. In addition, other proteins such as AGS3-6 can compete with Gβγ for binding to GDP bound Gα. This competition can promote Gβγ signaling by freeing Gβγ from rapidly rebinding GDP bound Gα. The proteins that participate in these non-canonical signaling pathways will be briefly described and their role, or potential one, in cells of the immune system will be highlighted.

Keywords: G-protein signaling; Immune system; Non-canonical; Ric-8A.

Figure 1. Involvement of heterotrimeric Gα proteins in the immune system

Schematic representation of the immune system. Hematopoiesis originates from hematopoietic stem cells (HSC). Multipotent progenitors (MPP) give rise to common lymphoid (CLP) through early lymphoid precursor (ELP) or myeloid (CMP) progenitors. CLPs initiate the B/T cell lineages through early-thymic-progenitors (ETP) and pro-B cells (Fr. A), respectively. ETPs develop through CD4⁻CD8⁻ (DN) and CD4⁺CD8⁺ (DP) stages into mature T cells and Natural killer T (NKT) cells. In the bone-marrow, pro-B cells develop via pre-B (Fr. D) cells into immature B cells (Fr. E). These translocate into the spleen to mature through transitional stages into mature B cells. Fetal liver HSC are responsible for the biogenesis of B1 cells. The ELP give rise to mature natural killer cells (mNK) found in the spleen generated in the bone marrow from progenitor (NKP) and immature (iNK). CMPs give rise to granulocyte–monocyte (GMP) and megakaryocyte–erythrocyte (MEP) progenitors and the indicated mature cell types.