The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure signal fidelity. A rapid overshoot in insulin-stimulated recruitment of Akt to the plasma membrane has previously been reported, which is indicative of negative feedback operating on acute timescales. Here, we show that Akt itself engages this negative feedback by phosphorylating insulin receptor substrate (IRS) 1 and 2 on a number of residues. Phosphorylation results in the depletion of plasma membrane-localised IRS1/2, reducing the pool available for interaction with the insulin receptor. Together these events limit plasma membrane-associated PI3K and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis. We identified two Akt-dependent phosphorylation sites in IRS2 at S306 (S303 in mouse) and S577 (S573 in mouse) that are key drivers of this negative feedback. These findings establish a novel mechanism by which the kinase Akt acutely controls PIP3 abundance, through post-translational modification of the IRS scaffold.
Edited by Jeffrey PessinHyperinsulinemia, which is associated with aging and metabolic disease, may lead to defective protein homeostasis (proteostasis) due to hyperactivation of insulin-sensitive pathways such as protein synthesis. We investigated the effect of chronic hyperinsulinemia on proteostasis by generating a time-resolved map of insulin-regulated protein turnover in adipocytes using metabolic pulse-chase labeling and high resolution mass spectrometry. Hyperinsulinemia increased the synthesis of nearly half of all detected proteins and did not affect protein degradation despite suppressing autophagy. Unexpectedly, this marked elevation in protein synthesis was accompanied by enhanced protein stability and folding and not by markers of proteostasis stress such as protein carbonylation and aggregation. The improvement in proteostasis was attributed to a coordinate upregulation of proteins in the global proteostasis network, including ribosomal, proteasomal, chaperone, and endoplasmic reticulum/mitochondrial unfolded protein response proteins. We conclude that defects associated with hyperactivation of the insulin signaling pathway are unlikely attributed to defective proteostasis because up-regulation of protein synthesis by insulin is accompanied by up-regulation of proteostatic machinery. The insulin signaling pathway (ISP)4 is a master regulator of protein metabolism. Many of its effects, such as increased protein synthesis and reduced autophagy, are orchestrated via mTORC1 (1, 2). The ISP is hyperactivated by chronic hyperinsulinemia, a common consequence of insulin resistance and aging (3). This in turn exacerbates insulin resistance, obesity (4 -6), and aging (7-10). Chronic ISP activity may partially cause these detrimental effects by dysregulating protein homeostasis (proteostasis) (11,12). Supporting this view, genetic manipulations that lead to either endoplasmic reticulum (ER) stress, reduced proteasomal activity, or reduced autophagy are associated with insulin resistance in mice (13-15). Moreover, the mTORC1 inhibitor rapamycin extends lifespan in a range of animals, and in Drosophila these effects are at least in part due to reduced protein synthesis and enhanced autophagy (16).Proteins are made via a carefully orchestrated process that minimizes misfolding. This involves chaperones that ensure efficient folding of newly synthesized proteins, the ubiquitinproteasome system that degrades misfolded proteins, and autophagy for removal of protein aggregates (17, 18). It has been proposed that chronic insulin signaling impairs protein folding and promotes aggregation because it simultaneously activates protein synthesis, suppresses autophagy, and inhibits the activity of FOXO, a transcription factor that regulates chaperone gene expression (11, 12, 19 -21).The effect of loss of function of daf-2/ISP activity on global proteostasis was recently studied in Caenorhabditis elegans (22), but few studies have examined the effects of hyperactivation of the ISP on proteostasis, and none have examined the...
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