Glia maturation factor-gamma modulation of signaling pathways in macrophages

National Heart, Lung, And Blood Institute

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Abstract

Arp2/3-mediated actin disassembly is a crucial process for cellular functions like cell motility, endocytosis, autophagy, and phagocytosis. Glia maturation factor-gamma (GMFG) is an actin-disassembly protein that binds to the Arp2/3 complex and directly induces debranching of actin filaments. GMFG has been implicated in cell migration, but whether it has a role in modulating autophagy and phagocytosis remains unknown. Here, we show that knockdown of GMFG inhibits autophagosome formation by suppressing LC3B lipidation in murine macrophages under both basal and autophagy-induction conditions. Moreover, induction of mitochondrial damage in GMFG-knockdown cells with the iron chelator deferiprone (DFP) or carbonyl cyanide 3-chlorophenylhydrazone (CCCP), as a model of selective autophagy of mitochondria (mitophagy), revealed that GMFG contributes to the mitochondrial targeting for autophagosome and autophagic degradation in response to DFP and CCCP treatment. GMFG knockdown also compromised lysosomal function. Further, GMFG knockdown suppressed phosphorylation of components of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway, suggesting a role for this pathway in GMFG regulation of autophagy and mitophagy. In addition, GMFG-knockdown macrophages displayed increased expression of the scavenger receptors MSR1 and CD36 and exhibited increased phagocytic activity. Conversely, overexpression of GMFG in murine macrophages increased autophagosome formation and suppressed phagocytosis mediated by both scavenger receptors. Taken together, these findings suggest that GMFG regulates autophagy and mitophagy associated with AMPK-regulated autophagosome formation and mediates phagocytosis through modulation of scavenger-receptor abundance in macrophages. These results may provide insight into therapeutic approaches to autophagy- or mitophagy-related diseases and phagocytosis in immune and metabolic disorders.