Ecto-F1-ATPase: A moonlighting protein complex and an unexpected apoA-I receptor

Figure 2 Model of the leading hypotheses regarding the distinct cellular events mediated by ecto-F₁-ATPase. (1) Model of F₁-ATPase/P2Y₁₃-mediated high density lipoproteins (HDL) endocytosis by hepatocytes. ApoA-I binding to ecto-F₁-ATPase stimulates extracellular ATP hydrolysis, and the ADP generated selectively activates the nucleotide receptor P2Y₁₃ and subsequent RhoA/ROCK I signaling that controls holo-HDL particle endocytosis. Conversely IF₁ inhibitor which inhibits ecto-F₁-ATPase activity or adenylate kinase (AK) activity which consumes ADP generated upon activation of ecto-F₁-ATPase, downregulates holo-HDL particle endocytosis. Thus, HDL endocytosis depends on the balance between the AK activity that removes extracellular ADP and the ecto-F₁-ATPase that synthesizes ADP. Activation of ADP synthesis by apoA-I unbalances the pathway and increases HDL endocytosis when required; (2), (3): Model of F₁-ATPase-mediated endothelial cell protection. (2): Hydrolytic activity of ecto-F₁-ATPase expressed on endothelial cells can be increased by apoA-I, stimulating cell proliferation. Conversely, inhibition by IF₁, angiostatin increases apoptosis and blocks proliferation both at the basal level and after stimulation by apoA-I. The downstream receptors and intracellular signaling are still not completely characterized, but ADP-sensitive receptors could be involved; (3): The anti-angiogenic activity of angiostatin is attributed to its ability to inhibit ATP production by ecto-F₁-ATPase, thus eliminating a significant source of energy and reducing proliferation. It is also proposed that this inhibition prevents the extrusion of protons by ecto-F₁-ATPase, thus lowering intracellular pH and hampering cell survival; and (4) Model of F₁-ATPase-mediated tumor cell recognition by Vγ9/Vδ2 T lymphocytes. Ecto-F₁-ATPase is found at the surface of tumor cells and plays a role in the presentation of adenylated derivatives of small phosphoantigens, which are classical inducers of cell lysis by Vγ9/Vδ2 T lymphocytes. Recognition of ecto-F₁-ATPase by the γ9/δ2 TCR is stimulated by apoA-I and requires a low expression of class I HLA-antigens, a situation commonly found in tumor cells.