G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis

Abstract

Polymorphism at the GPSM3 gene locus is inversely associated with four systemic autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis. G-protein signaling modulator-3 (GPSM3) expression is most pronounced in myeloid cells, in which it targets heterotrimeric G-protein Gαi subunits of chemokine receptors, critical to immune function. To begin to explore the regulatory role of GPSM3 in monocytes, human THP-1 and primary mouse myeloid cells were cultured under stimulus conditions; GPSM3 was found by immunoblotting to be expressed at highest levels in the mature monocyte. To evaluate the effects of GPSM3 deficiency on a myeloid-dependent autoimmune disease, Collagen Antibody-Induced Arthritis (CAIA) was induced in Gpsm3−/− and control mice, which were then analyzed for clinical score, paw swelling, intra-articular proinflammatory markers, and histopathology. Mice lacking GPSM3 were protected from CAIA, and expression of monocyte-representative pro-inflammatory chemokine receptors and cytokines in paws of Gpsm3−/− mice were decreased. Flow cytometry, apoptosis, and transwell chemotaxis experiments were conducted to further characterize the effect of GPSM3 deficiency on survival and chemokine responsiveness of monocytes. GPSM3-deficient myeloid cells had reduced migration ex vivo to CCL2, CX3CL1, and chemerin and enhanced apoptosis in vitro. Our results suggest that GPSM3 is an important regulator of monocyte function involving mechanisms of differentiation, survival, and chemotaxis, and deficiency in GPSM3 expression is protective in acute inflammatory arthritis.

Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4)

“…The location of the Gpsm3 gene within the class III major histocompatibility class locus suggested that AGS4/Gpsm3 is expressed primarily in the immune system, and initial observations from us and others indicated this was indeed the case (Cao et al, 2004;Kimple et al, 2004;Zhao et al, 2010;Schmidt et al, 2012;Giguère et al, 2013). We also discovered AGS4 expression in primary bone marrow-derived dendritic cells and splenocytes (Fig.…”

“…A growing number of cellular and physiologic roles have been ascribed to GPR proteins in systems where signal modulation and adaptation are critical for system responsiveness (Bowers et al, 2004(Bowers et al, , 2008Yao et al, 2005Yao et al, , 2006Blumer et al, 2008;Nadella et al, 2010;Regner et al, 2011;Chauhan et al, 2012;Kwon et al, 2012;Giguère et al, 2013;Kamakura et al, 2013;Branham-O'Connor et al, 2014;Singh et al, 2014). The immune system is certainly an area rich in signaling modulation and adaptation and requires dynamic signal processing and spatially integrated G-protein signaling (Cho and Kehrl, 2009;Kehrl et al, 2009).…”

Canonical and Noncanonical G-Protein Signaling Helps Coordinate Actin Dynamics To Promote Macrophage Phagocytosis of Zymosan

“…We are currently testing whether reducing the expression of these proteins impacts phagocytosis. Suggesting that they may have functional roles, myeloid cells from Gpsm3 Ϫ/Ϫ mice migrate less efficiently to Ccl2 and Cx3cl1 than do wild-type mouse myeloid cells (45). Importantly, many of these proteins have additional domains that can interact with other relevant proteins.…”

G Protein Signaling Modulator-3 Inhibits the Inflammasome Activity of NLRP3

“…Some of us have recently described functional studies of G protein signaling modulator-3 (GPSM3), a newly identified signaling regulator with prominent expression in myeloid lineage cells and lower relative expression levels in other hematopoietic lineages as well as non-hematopoietic tissues (16). GPSM3 (a.k.a.…”

“…AGS4 or G18; Ref. 17,18) possesses two functional "GoLoco motifs" (18) for binding heterotrimeric G protein G␣ i subunits and additionally binds to G␤ subunits during their synthetic pathway toward forming mature G␤␥ dimers (19); these interactions with heterotrimeric G protein subunits are thought to underlie the effects of GPSM3 on chemokine receptor signaling that is critical to the development of inflammatory arthritis (16). More recently, we have described GPSM3 as also interacting directly with the adaptor protein 14-3-3 (20).…”