SNX3 recruits to phagosomes and negatively regulates phagocytosis in dendritic cells

Abstract

SummaryPhagocytes such as dendritic cells (DC) and macrophages employ phagocytosis to take up pathogenic bacteria into phagosomes, digest the bacteria and present the bacteria-derived peptide antigens to the adaptive immunity. Hence, efficient antigen presentation depends greatly on a well-regulated phagocytosis process. Lipids, particularly phosphoinositides, are critical components of the phagosomes. Phosphatidylinositol-3,4,5-triphosphate [PI(3,4,5)P 3 ] is formed at the phagocytic cup, and as the phagosome seals off from the plasma membrane, rapid disappearance of PI(3,4,5)P 3 is accompanied by high levels of phosphatidylinositol-3-phosphate (PI3P) formation. The sorting nexin (SNX) family consists of a diverse group of Phox-homology (PX) domain-containing cytoplasmic and membrane-associated proteins that are potential effectors of phosphoinositides. We hypothesized that SNX3, a small sorting nexin that contains a single PI3P lipid-binding PX domain as its only protein domain, localizes to phagosomes and regulates phagocytosis in DC. Our results show that SNX3 recruits to nascent phagosomes and silencing of SNX3 enhances phagocytic uptake of bacteria by DC. Furthermore, SNX3 competes with PI3P lipid-binding protein, early endosome antigen-1 (EEA1) recruiting to membranes. Our results indicate that SNX3 negatively regulates phagocytosis in DC possibly by modulating recruitment of essential PI3P lipid-binding proteins of the phagocytic pathways, such as EEA1, to phagosomal membranes.

SNX10 promotes phagosome maturation in macrophages and protects mice againstListeria monocytogenesinfection

“…Phagocytosis by macrophages for ingestion and degradation of microbes is not only the first line of defense in the innate immune response to infection but is also important for antigen processing and presentation, which helps to drive the adaptive immune response. Although some SNX family proteins, such as SNX3 and SNX5 [ 29 , 30 ], have been shown to affect phagocytosis, our results suggested that SNX10 deficiency did not affect the phagocytosis of macrophages following bacterial infection. However, loss of SNX10 decreased the efficiency of killing L. monocytogenes .…”

SNX3 drives maturation of Borrelia phagosomes by forming a hub for PI(3)P, Rab5a, and galectin-9

“…Importantly, SNX3 has been described to localize to phagosomes in human dendritic cells ( Chua and Wong, 2013 ) and to SCVs in HeLa cells ( Braun et al, 2010 ), the latter also involving PI(3)P, Rab5, and the generation of membrane tubules. However, there are important differences between these earlier models and the pathway that we describe here.…”

Two isotypes of phosphatidylinositol 3‐phosphate ‐ binding sorting nexins play distinct roles in trogocytosis in Entamoeba histolytica

“…The fact that gene silencing of EhSNX2, but not EhSNX1, increased the trogocytosis efficiency was counter-intuitive and suggestive of EhSNX2 being a negative regulator of trogocytosis. It has been shown that in dendritic cells, SNX3 overexpression causes defect in early endosome maturation by competing PI3P on early endosomes and reducing EEA1 recruitment (Chua & Wong, 2013). This observed phenotype may mirror the apparent upregulation of trogocytosis by…”

“…It has been shown that in dendritic cells, SNX3 overexpression causes defect in early endosome maturation by competing PI3P on early endosomes and reducing EEA1 recruitment (Chua & Wong, 2013). It has been shown that in dendritic cells, SNX3 overexpression causes defect in early endosome maturation by competing PI3P on early endosomes and reducing EEA1 recruitment (Chua & Wong, 2013).…”