Glia maturation factor-γ regulates amyloid-β42 phagocytosis through scavenger receptor AI in murine macrophages

Abstract

Abstract Dysfunctional phagocytic clearance of β-amyloid (Aβ) in microglia and peripheral macrophages/monocytes has been implicated in Alzheimer’s disease (AD), but the mechanisms underlying this dysfunction are not yet well understood. In this study, we examined the role of glia maturation factor-γ (GMFG), an actin-disassembly protein that is highly expressed in immune cells, in macrophage Aβ phagocytosis and in regulating scavenger receptor AI (SR-AI), a cell-surface receptor that has previously been implicated in Aβ clearance. GMFG knockdown increased phagocytosis of Aβ42 in BMDMs and RAW264.7 murine macrophages, while GMFG overexpression reduced Aβ42 uptake in these cells. Blocking with anti-SR-AI antibodies inhibited Aβ42 uptake in GMFG-knockdown cells, establishing a role for SR-AI in Aβ42 phagocytosis. GMFG knockdown increased SR-AI protein expression under both basal conditions and in response to Aβ42 treatment via both the transcriptional and post-transcriptional level in RAW264.7 macrophages. GMFG knockdown modulated Aβ42-induced K48-linked and K63-polyubiquitination of SR-AI, the phosphorylation of SR-AI and JNK, suggesting that GMFG plays a role for intracellular signaling in the SR-AI–mediated uptake of Aβ. Further, GMFG-knockdown cells displayed increased levels of the transcriptional factor MafB, and silencing of MafB in these cells reduced their SR-AI expression. Finally, GMFG was found to interact with the nuclear pore complex component RanBP2, and silencing of RanBP2 in GMFG-knockdown cells reduced their SR-AI expression. Collectively, these data support the role of GMFG as a novel regulator of SR-AI in macrophage Aβ phagocytosis, and may provide insight into therapeutic approaches to potentially slow or prevent the progression of AD.