ReviewThe impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity
Graphical abstract
Introduction
Upon ligand binding chemoattractant GPCRs undergo conformational rearrangements that change their interaction with signal transducer proteins [1], [2], [3]. The major proximal signal transducers of an activated GPCR are their cognate heterotrimeric G-proteins, although ligand activated GPCRs engage other proteins including G-protein receptor kinases (GRKs) and β-arrestins [4], [5], [6]. Chemoattractant receptors predominately couple to the Gi family of heterotrimeric G-proteins as their signaling is sensitive to treatment with pertussis toxin, which ADP ribosylates a cysteine residue near the C-termini of αi subunit [7], [8]. This inhibits Gαi from undergoing GPCR-mediated nucleotide exchange. The GTP/GDP binding status of Gαi controls its interaction with the other members of the trimeric G protein, the Gβγ dimer [2], [9]. Composed of one of 5 β and one of 12 γ subunits, the Gβγ dimers, once assembled, are inseparable. Receptor activation and Gαi subunit nucleotide exchange causes the Gαi subunit and Gβγ subunits to functionally dissociate. GTP bound Gαi and the freed Gβγ can then engage downstream effector molecules. However, it is the Gβγ effectors that are the most crucial for gradient sensing and directional cell migration [10]. The activated Gα subunits remain only transiently GTP bound as they possess an intrinsic GTPase activity, which converts their bound GTP to GDP. This encourages the reassembly of the heterotrimeric G-protein terminating signaling, but also allows the G-protein to engage other activated receptors, thereby initiating another round of signaling. The intrinsic GTPase activity of Gα subunits can be greatly enhanced by GTPase activating proteins termed GAPs. Most Gαi GAPs contain a Regulator of G-protein Signaling (RGS) domain [11], [12], [13]. Other G-protein regulatory proteins include those that have a G-protein regulatory (GPR) domain, also called a GoLoco motif, which acts as a guanine nucleotide dissociation inhibitor (GDI) much like Gβγ [14], [15], [16]. Both RGS and GPR domain containing proteins impact Gi signaling. This review will focus predominately on the Gαi proteins and their regulators in the context of chemokine and chemoattractant receptor signaling.
Section snippets
Gi proteins
The heterotrimeric G proteins are divided into four classes; Gi, Gq, G12/13, and Gs, based on the amino acid sequences of their α subunit [2]. The expression levels of the various Gα subunits in murine leukocytes based on mRNA sequencing are shown in Table 1. The “inhibitory class” of heterotrimeric G-proteins were originally named based on the ability of Gi/o proteins to inhibit adenylyl cyclase activity. Based on amino acid sequence homology the Gi family now includes not only Gi/o, but also
Ric-8A
Ric-8 was identified in Caenorhabditis elegansbased on its role in asymmetric cell divisions during early development [58], [59], [60]. A human homolog, Ric-8A, was shown to recruit a signaling complex to the cell cortex that helped orient the mitotic spindle in response to spatial clues [61]. Targeting ric8 in mice caused early embryonic lethality, however, derived ric8−/− embryonic cell lines had pleiotropic G protein signaling defects and major losses of Gαi1/2, Gαq, and Gα13 proteins due to
Conclusions
Many of the GPCRs expressed by leukocytes function as chemoattractant receptors. The signals emanating from these receptors recruit leukocytes to inflammatory sites; organize the positioning of leukocytes in immune organs, help maintain the overall architecture of immune organs; coordinate the movements of leukocytes through tissues; and facilitate the trafficking of leukocytes into and out of lymph nodes, the bone marrow, skin, and the gut associated lymphoid tissues (GALT). The signaling
Conflict of interest
There are no conflict of interests.
Acknowledgements
The author would like to thank the members of his laboratory that contributed to some of the studies described in this review and thank Dr. Anthony Fauci for his long standing support. The intramural program of the National Institutes of Allergy and Infectious Diseases supported some of the research described in this review.
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