Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, The Rockefeller University, New York, NY, USA.
Nature. 2023 May;617(7962):798-806. doi: 10.1038/s41586-023-06039-y. Epub 2023 May 3.
Inorganic phosphate (P) is one of the essential molecules for life. However, little is known about intracellular P metabolism and signalling in animal tissues. Following the observation that chronic P starvation causes hyperproliferation in the digestive epithelium of Drosophila melanogaster, we determined that P starvation triggers the downregulation of the P transporter PXo. In line with P starvation, PXo deficiency caused midgut hyperproliferation. Interestingly, immunostaining and ultrastructural analyses showed that PXo specifically marks non-canonical multilamellar organelles (PXo bodies). Further, by P imaging with a Förster resonance energy transfer (FRET)-based P sensor, we found that PXo restricts cytosolic P levels. PXo bodies require PXo for biogenesis and undergo degradation following P starvation. Proteomic and lipidomic characterization of PXo bodies unveiled their distinct feature as an intracellular P reserve. Therefore, P starvation triggers PXo downregulation and PXo body degradation as a compensatory mechanism to increase cytosolic P. Finally, we identified connector of kinase to AP-1 (Cka), a component of the STRIPAK complex and JNK signalling, as the mediator of PXo knockdown- or P starvation-induced hyperproliferation. Altogether, our study uncovers PXo bodies as a critical regulator of cytosolic P levels and identifies a P-dependent PXo-Cka-JNK signalling cascade controlling tissue homeostasis.
无机磷酸盐（P）是生命必需的分子之一。然而，动物组织中细胞内 P 代谢和信号转导的知识知之甚少。在观察到慢性 P 饥饿导致果蝇黑腹果蝇消化上皮过度增殖之后，我们确定 P 饥饿会触发 P 转运蛋白 PXo 的下调。与 P 饥饿一致，PXo 缺乏导致中肠过度增殖。有趣的是，免疫染色和超微结构分析表明 PXo 特异性标记非典型的多层细胞器（PXo 体）。此外，通过基于Förster 共振能量转移（FRET）的 P 传感器进行 P 成像，我们发现 PXo 限制了细胞质中的 P 水平。PXo 体的生物发生需要 PXo，并在 P 饥饿后降解。对 PXo 体的蛋白质组学和脂质组学分析揭示了它们作为细胞内 P 储备的独特特征。因此，P 饥饿会触发 PXo 的下调和 PXo 体的降解，作为增加细胞质 P 的补偿机制。最后，我们确定了连接蛋白激酶到 AP-1（Cka），STRIPAK 复合物的一个组成部分和 JNK 信号，作为 PXo 敲低或 P 饥饿诱导的过度增殖的介导物。总之，我们的研究揭示了 PXo 体作为细胞质 P 水平的关键调节剂，并确定了一个依赖于 P 的 PXo-Cka-JNK 信号级联，控制组织动态平衡。
