Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月27日

查看全文
  • Emily Meeus,
  • Elke Ausloos,
  • Chris Van den Haute,
  • Jan Eggermont,
  • Sarah van Veen,
  • Peter Vangheluwe

摘要

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.