Regulation of longevity by regulator of G-protein signaling protein, Loco

Abstract

SummaryRegulator of G-protein signaling (RGS) proteins contribute to G-protein signaling pathways as activators or repressors with GTPase-activating protein (GAP) activity. To characterize whether regulation of RGS proteins influences longevity in several species, we measured stress responses and lifespan of RGS-overexpressing and RGSlacking mutants. Reduced expression of Loco, a RGS protein of Drosophila melanogaster, resulted in a longer lifespan for both male and female flies, also exhibiting stronger resistance to three different stressors (starvation, oxidation, and heat) and higher manganese-containing superoxide dismutase (MnSOD) activity. In addition, this reduction in Loco expression increased fat content and diminished cAMP levels. In contrast, overexpression of both genomic and cDNA loco gene significantly shortened the lifespan with weaker stress resistance and lower fat content. Deletion analysis of the Loco demonstrated that its RGS domain is required for the regulation of longevity. Consistently, when expression of RGS14, mammalian homologue of Loco, was reduced in rat fibroblast cells, the resistance to oxidative stress increased with higher MnSOD expression. The changes of yeast Rgs2 expression, which shares a conserved RGS domain with the fly Loco protein, also altered lifespan and stress resistance in Saccharomyces cerevisiae. Here, we provide the first evidence that RGS proteins with GAP activity affect both stress resistance and longevity in several species.

Loco signaling pathway in longevity

“…The induced ERK phosphorylation in AC-PKA and Ras-Raf-MEK-ERK signaling pathways is known to activate anti-apoptosis, cell survival and anti-oxidative stress mechanisms in yeast and mammals. 6,7 Based on the previous reports in reference 6, 7, 14-16, 26-27 and our results 25 including Figure 1, it is likely that the Loco protein regulates stress resistance and longevity by modulating ERK phosphorylation through at least two mechanisms ( Fig. 2): first, the RGS domain-dependent inactivation of the inhibitory Gαi protein, which results in the activation of the AC-cAMP-PKA pathway and the inactivation of Raf; and second, the RBD domain-dependent inhibition of active Ras/Raf as a molecular scaffold to sequester their functions.…”

“…Changes of yeast RGS2 expression produced different amounts of cAMP 22 and altered stress resistance and lifespan in Saccharomyces cerevisiae. 25 The mammalian RGS14 protein is 80% homologous Loco protein also interacts with the monomeric G proteins Rap1, Rap2 and Ras1 (small GTPase). 16 Nevertheless, the signaling pathway downstream of Loco has not been studied in detail.…”

“…14 Deletion analysis of RGS and GoLoco domains 25 showed that the GAP activity of the Loco RGS domain may be important for the regulation of the aging process. The RGS proteins (RGS2, Loco and RGS14) may be involved globally in the biological processes of stress resistance and lifespan in several species as upstream regulators of longevity signaling pathway beyond the specific cellular functions.…”

E-Government Diffusion in Jordan: Employees' Perceptions Toward Electronic Government in Jordan

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