Abstract
Fluid-phase pinocytosis of LDL by macrophages is regarded as a novel promising target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. The mechanisms of regulation of fluid-phase pinocytosis in macrophages and, specifically, the role of Akt kinases are poorly understood. We have found previously that increased lipoprotein uptake via the receptor-independent process in Akt3 kinase-deficient macrophages contributes to increased atherosclerosis in Akt3-/- mice. The mechanism by which Akt3 deficiency promotes lipoprotein uptake in macrophages is unknown. We now report that Akt3 constitutively suppresses macropinocytosis in macrophages through a novel WNK1/SGK1/Cdc42 pathway. Mechanistic studies have demonstrated that the lack of Akt3 expression in murine and human macrophages results in increased expression of with-no-lysine kinase 1 (WNK1), which, in turn, leads to increased activity of serum and glucocorticoid-inducible kinase 1 (SGK1). SGK1 promotes expression of the Rho family GTPase Cdc42, a positive regulator of actin assembly, cell polarization, and pinocytosis. Individual suppression of WNK1 expression, SGK1, or Cdc42 activity in Akt3-deficient macrophages rescued the phenotype. These results demonstrate that Akt3 is a specific negative regulator of macropinocytosis in macrophages.
Highlights
Fluid-phase pinocytosis of LDL by macrophages is regarded as a novel promising target to reduce macrophage cholesterol accumulation in atherosclerotic lesions
We report that Akt3 constitutively suppresses macropinocytosis in macrophages through a novel with-no-lysine kinase 1 (WNK1)/serum and glucocorticoid-inducible kinase 1 (SGK1)/Cdc42 pathway
Akt3 deficiency leads to increased uptake of LDL via macropinocytosis in murine and in human macrophages
Summary
Fluid-phase pinocytosis of LDL by macrophages is regarded as a novel promising target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. Individual suppression of WNK1 expression, SGK1, or Cdc activity in Akt3-deficient macrophages rescued the phenotype These results demonstrate that Akt is a specific negative regulator of macropinocytosis in macrophages. Our recent study demonstrated that the lack of Akt expression in macrophages promotes atherosclerosis via increased accumulation of cholesterol via enhanced receptor-independent uptake of LDL and increased expression of ACAT1 by these cells [21]. We found that Akt controls a novel pathway of actin-dependent macropinocytosis in macrophages by suppressing the expression of WNK2 and activity of SGK1, two kinases that have not been implicated previously in pinocytosis. SU6656 and cytochalasin D abolished increased pinocytosis in Akt3Ϫ/Ϫ macrophages (Fig. 2A), suggesting that a loss of Akt in MPMs stimulates actin-dependent macropinocytosis but not micropinocytosis. Cholesterol accumulation in human MDM with suppressed expression of Akt was inhibited by SU6656 and cytochalasin D (Fig. 2B)
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