Guanine Nucleotide-Binding Proteins of the G12 Family Shape Immune Functions by Controlling CD4+ T Cell Adhesiveness and Motility

Abstract

Integrin-mediated adhesion plays a central role in T cell trafficking and activation. Genetic inactivation of the guanine nucleotide-binding (G) protein alpha-subunits Galpha(12) and Galpha(13) resulted in an increased activity of integrin leukocyte-function-antigen-1 in murine CD4(+) T cells. The interaction with allogeneic dendritic cells was enhanced, leading to an abnormal proliferative response in vitro. In vivo, T cell-specific inactivation of Galpha(12) and Galpha(13) caused lymphadenopathy due to increased lymph node entry and enhanced T cell proliferation, and the susceptibility toward T cell-mediated diseases was enhanced. Mechanistically, we show that in the absence of Galpha(12) and Galpha(13) the activity of the small GTPases Rac1 and Rap1 was increased, whereas signaling of the small GTPase RhoA was strongly reduced. Our data indicate that locally produced mediators signal through Galpha(12)- and Galpha(13)-coupled receptors to negatively regulate cell polarization and adhesiveness, thereby fine-tuning T cell trafficking, proliferation, and susceptibility toward T cell-mediated diseases.

Proteomic responses reveal the differential effects induced by cadmium in mussels Mytilus galloprovincialis at early life stages

“…Surprisingly, four proteins (peptidylprolyl isomerase A, guanine nucleotide-binding protein G(o) subunit alpha, sorting nexin 6 and collagen alpha-6(VI) chain isoform X3) involved in signal transduction were significantly altered in Cd-treated juvenile mussels. Among these four proteins, guanine nucleotide-binding protein plays an important role in immune functions [33]. The downregulation of this protein confirmed the immune stress induced by Cd in juvenile mussels, as marked by the down-regulated apextrin-like protein.…”

Novel lysophosphoplipid receptors: their structure and function

“…G ␣ 12/13 signaling in T cells has a role to downregulate the cellular function of T cells. Genetic inactivation of both G ␣ 12 and G ␣ 13 genes enhanced the proliferation and adhesive properties of T cells ( 52 ). Interestingly, LysoPS suppressed the proliferation of activated T cells in vitro ( 24 ), which raises the possibility that LysoPS has its role in T cells through P2Y10.…”

S1P 2 /G 12/13 Signaling Negatively Regulates Macrophage Activation and Indirectly Shapes the Atheroprotective B1-Cell Population

“…Samples were lysed in 1X Triton-X buffer containing 20mM Tris-HCL pH7,5, 150mM NaCl, 1mM EDTA, 1mM EGTA, 1% Triton-X, 2,5mM sodium pyrophosphate, 1mM beta-glycerophosphate, 1mM Na 3 VO 4 20 and 1µg/ml leupeptin, subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), transferred to nitrocellulose transfer membranes (Whatman, Dassel, Germany), and then incubated over night with primary antibodies (1:500) as indicated. After washing in 1X TBST for three times, membranes were incubated with horseradish peroxidase-conjugated secondary antibodies (1:3000) for 2h.…”

“…[17][18][19] Studies in mice with T-cell-or B-cellspecific deficiency for Gα 12/13 showed that this G-protein family is intricately linked to the regulation of actomyosin-based contractility and cytoskeletal rearrangement, thereby controlling cell shape, migration, and adhesiveness. 20,21 Although no in vivo data exist, it was suggested that this holds also true in myeloid cells because expression of dominant negative Gα 12 and Gα 13 disturbs polarization in a neutrophil cell line, resulting in cells containing multiple leading edges. 22 In addition, G 12/13 -coupled receptors have been implicated in the NF-κB and SRF-dependent regulation of gene transcription in a variety of cell types.…”