ATP13A4 sensitizes cells to polyamine-induced cytotoxicity in a SAT1-dependent manner

Abstract Polyamines are essential metabolites whose intracellular levels must be tightly controlled, as excessive accumulation perturbs cellular homeostasis and viability. Although polyamine transport is a major determinant of intracellular polyamine burden, how transport processes influence cellular responses to polyamine excess remains incompletely understood. Here, we identify the P5-type ATPase ATP13A4 as a transport-dependent regulator of cellular sensitivity to polyamines. Using complementary gain- and loss-of-function cellular models, we demonstrate that ATP13A4 modulates the cellular sensitivity to polyamine toxicity. Expression of functional ATP13A4 sensitized cells to polyamine-induced loss of viability and cell death, whereas a transport-deficient mutant or depletion of endogenous ATP13A4 conferred protection. This effect could not be explained by extracellular amine oxidation. ATP13A4 expression increased cellular dependence on spermidine/spermine N¹-acetyltransferase 1 (SAT1), and pharmacological SAT1 inhibition markedly exacerbated polyamine-induced cytotoxicity. ATP13A4-dependent uptake was further associated with activation of JNK-linked stress signaling, and JNK inhibition partially attenuated cell death. Collectively, these findings indicate that ATP13A4-mediated polyamine uptake sensitizes cells to polyamines, increasing reliance on SAT1-dependent buffering against excessive polyamine levels and engaging stress signaling pathways when the polyamine buffering capacity is exceeded.