Role of ADAR1 in human macrophages

This study aims to delineate the role of ADAR1 in human cells beyond its canonical function as an interferon-stimulated gene (ISG). Human monocyte-derived macrophages were subjected to RNA interference targeting either pan-ADAR1 (both isoforms) or the p150 isoform specifically. Quantitative proteomic analyses were performed using state-of-the-art isobaric tandem mass tag (TMT) labeling coupled with liquid chromatography–tandem mass spectrometry (LC-MS/MS). Strikingly, silencing of ADAR1 significantly impacted prototypical macrophage functions, including endocytosis, cholesterol metabolism, and lysosomal processing, without concurrent induction of pro-inflammatory or ISG responses. Pan-ADAR1 silencing resulted in upregulation of proteins involved in lysosomal function and cholesterol processing, whereas selective depletion of ADAR1-p150 led to downregulation of pathways associated with phagocytosis and endocytosis. Moreover, loss of pan-ADAR1 caused a marked downregulation of cell-cycle and p53 signaling pathways, suggesting a potential role for the ADAR1-p110 isoform in regulating cell proliferation. Collectively, these data define previously unappreciated proteomic alterations driven by ADAR1 that influence fundamental macrophage functions beyond its established ISG role.