Synergistic Activity of APOL3 and GBP1 in Antigen Cross-Presentation: A Model

Antigen cross-presentation by dendritic cells allows the induction of an immune response (activation of cytotoxic CD8⁺ T cells) against internalized components from pathogens or dying tumour cells, through export of these components from the lumen of phagosomes to the cell surface. Such export requires megapore formation in the phagolysosomal membrane, as also occurs in the outer membrane of mitochondria for cytochrome c export during apoptosis. Two interferon-induced proteins synergistically participate in this process: apolipoprotein L3 (APOL3) (or its murine homologue mAPOL7C) and the dynamin-like GTPase guanylate-binding protein-1 (GBP1). In this Perspective, it is proposed that phagolysosomal membrane disorganization by GBP1 allows pore formation by APOL3, through transmembrane insertion and cardiolipin solubilization. Moreover, both proteins could induce activation of non-muscle myosin 2A (NM2A) and pro-apoptotic BCL2-associated protein X (BAX), which allow phagolysosomal and mitochondrial pore expansion and stabilization into open megapores. Given the potential of its transmembrane α-helices for oligomerization, APOL3 may participate in the inner coating of phagolysosomal membrane megapores.