Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Medical School, Naples, Italy.
J Cell Biol. 2019 Mar 4;218(3):783-797. doi: 10.1083/jcb.201812021. Epub 2019 Jan 18.
Phosphatidylinositol-4-phosphate (PI4P), a phosphoinositide with key roles in the Golgi complex, is made by Golgi-associated phosphatidylinositol-4 kinases and consumed by the 4-phosphatase Sac1 that, instead, is an ER membrane protein. Here, we show that the contact sites between the ER and the TGN (ERTGoCS) provide a spatial setting suitable for Sac1 to dephosphorylate PI4P at the TGN. The ERTGoCS, though necessary, are not sufficient for the phosphatase activity of Sac1 on TGN PI4P, since this needs the phosphatidyl-four-phosphate-adaptor-protein-1 (FAPP1). FAPP1 localizes at ERTGoCS, interacts with Sac1, and promotes its in-trans phosphatase activity in vitro. We envision that FAPP1, acting as a PI4P detector and adaptor, positions Sac1 close to TGN domains with elevated PI4P concentrations allowing PI4P consumption. Indeed, FAPP1 depletion induces an increase in TGN PI4P that leads to increased secretion of selected cargoes (e.g., ApoB100), indicating that FAPP1, by controlling PI4P levels, acts as a gatekeeper of Golgi exit.
磷脂酰肌醇-4-磷酸（PI4P）是一种在高尔基体中起关键作用的磷酸肌醇，由高尔基体相关的磷脂酰肌醇-4 激酶合成，并被内质网膜蛋白 4-磷酸酶 Sac1 消耗。在这里，我们表明内质网和 TGN 之间的接触位点（ERTGoCS）提供了一个适合 Sac1 在 TGN 处去磷酸化 PI4P 的空间环境。尽管 ERTGoCS 是必需的，但不足以使 Sac1 在 TGN PI4P 上具有磷酸酶活性，因为这需要磷脂四磷酸接头蛋白-1（FAPP1）。FAPP1 定位于 ERTGoCS，与 Sac1 相互作用，并在体外促进其转位磷酸酶活性。我们设想，FAPP1 作为 PI4P 探测器和接头，将 Sac1 定位在 PI4P 浓度升高的 TGN 结构域附近，从而允许 PI4P 的消耗。事实上，FAPP1 的耗竭会导致 TGN PI4P 的增加，从而导致选定货物（例如 ApoB100）的分泌增加，表明 FAPP1 通过控制 PI4P 水平，作为高尔基体出口的守门员发挥作用。
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