Müller, C.; Casanova-Sepulveda, G.; Hernandez, A. B.; Mossmann, D.; Oppelt, M.; Carscadden, J. K.; Colombi, M.; Ritz, D.; Hall, M. N.

Intracellular polyamine levels are tightly regulated and frequently elevated in cancer. While the regulation of polyamine synthesis is well characterized, the regulation of polyamine uptake is poorly understood. Here we identify ATP13A3 as a plasma membrane polyamine transporter. An increase in intracellular polyamine levels, due to polyamine supplementation or induction of polyamine synthesis, causes rapid internalization of the transporter and inhibition of polyamine uptake. Mechanistically, increased polyamine concentrations lead to expression of antizyme (AZ) which binds ATP13A3 and triggers its internalization. Mutations in the AZ binding site of ATP13A3 prevent AZ binding and lead to polyamine toxicity through uncontrolled polyamine influx. These findings establish ATP13A3 as a key polyamine transporter and provide a framework for targeting polyamine metabolism in cancer.