F1-ATPase-related Structures

Short Introduction of F1-ATPase

The adenosine triphosphate (ATP) synthases, also known as F-ATPases or F1FoATPases, are multi-subunit enzymes found in energy-transducing membranes in mitochondria, chloroplasts, and eubacteria. They catalyze the synthesis of ATP from adenosine diphosphate (ADP) and inorganic phosphate by using energy from a transmembrane electrochemical gradient of protons, known as the proton motive force (or pmf).

The Involvement of F1-ATPase in Triggering T Cells Transduced with a Broadly Tumor-Reactive γ9δ2 TCR

To test whether recognition of F1-ATPase is a general mechanism by which γ9δ2 TCR G115-transduced αβ T cells recognize tumor cells, a panel of tumor and normal cells was stained for F1-ATPase surface expression. Most of the normal cells like αβ T cells, hepatocytes, and fibroblasts are stained-negative for F1-ATPase on their surface, while tumor cells had different levels of F1-ATPase expression. Some tumor cell lines (NB4, MZ1851RC, and SCC9) can be recognized by γ9δ2 TCR transduced αβ T cells in the absence of F1-ATPase expression, and other tumor cells (ML1 and HL60) with high expression of F1-ATPase were not recognized by γ9δ2 TCR transduced αβ T cells.

These results suggest that the interaction of the γ9δ2 TCR G115 with F1-ATPase is additive but not mandatory and alone is not sufficient for the activation of γ9δ2 TCR-transduced αβ T cells.

Fig.1 Role of F1-ATPase and NKG2D in the target recognition by γ9δ2 TCR-transduced αβ T cells. (Marcu-Malina, 2011)

The Ectopic Surface Expression of the F1-ATPase, Normally Expressed on the Internal Membrane of Mitochondria, was Implicated in Tumor Recognition of Vγ9Vδ2 T Cells

Different functions have been attributed to the ectopic expression of the F1-ATPase on the cell surface, including an immunoregulatory role induced by cell stress, the receptor for angiostatin, or regulation of lipoprotein transport through high-affinity apolipoprotein A-I binding. Importantly, F1-ATPase (recognized by monoclonal antibody 7H10) strongly correlates with the susceptibility of tumor cells against Vγ9Vδ2 T cell lysis. The α subunit of F1-ATPase was detected on several tumor cell lines which are consistently killed by activated Vγ9Vδ2 T cells (Daudi, K562, RPMI 8226), whereas the known Vγ9Vδ2 T cell resistant tumor cell lines (Raji, Jurkat) did not express detectable levels of the F1-ATPase.

The mAb against the α subunit of F1-ATPase significantly decreased in vitro lysis of myeloma cell lines and primary myeloma cells by activated Vγ9Vδ2 T cells. These results suggest Vγ9Vδ2 TCR-dependent interactions between myeloma cells and Vγ9Vδ2 T cells.

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Reference

1. Marcu-Malina, V.; et al. Redirecting αβ T cells against cancer cells by transfer of a broadly tumor-reactive γδ T-cell receptor. Blood. 2011, 118(1): 50-9.