Glia maturation factor-gamma modulation of signaling pathways in macrophages

National Heart, Lung, And Blood Institute

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Abstract

Autophagy and phagocytosis are critical processes involved in maintaining macrophage homeostasis and cellular immunity. Both pathways converge at the lysosome, within which cellular or extracellular material destined for removal by these pathways is subjected to lysosomal degradation. Because dysfunction of autophagy is observed in many human pathologies, it is important to understand the regulatory mechanisms governing crosstalk between autophagy and phagocytosis. Glia maturation factor-gamma (GMF-gamma) has been shown to regulate both the actin-related protein (Arp)2/3 complex and actin cytoskeleton reorganization, but its role in modulating autophagy and phagocytosis remains unknown. Here, we show that the knockdown of GMF-gamma inhibited autophagosome formation by suppressing LC3B lipidation and ATG9A trafficking in murine macrophages. Furthermore, knockdown of GMF-gamma also compromised lysosomal function by promoting the accumulation of p62/sequestosome 1 and decreased cathepsin D maturation. In addition, GMF-gamma knockdown suppressed phosphorylation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway components, suggesting a role for this pathway in GMF-gamma regulation of autophagy. Moreover, GMF-gamma-knockdown macrophages displayed increased expression of scavenger receptors MSR1 and CD36, dependent on activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, and exhibited increased phagocytic activity. In contrast, overexpression of GMF-gamma in murine macrophages increased autophagosome abundance and suppressed scavenger-receptor expression and phagocytic activity. These findings suggest that GMF-gamma regulates autophagy through AMPK-regulated control of autophagosome formation while mediating phagocytosis through modulation of scavenger-receptor abundance in macrophages and may provide insight into therapeutic approaches to autophagy-related diseases and autophagy-regulated phagocytosis in immune and metabolic disorders.