A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane.
A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane.
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DOI：
10.1242/jcs.261494
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发表时间：
2023-08-15
影响因子：
4
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脂质分子磷脂酰肌醇（4，5）-二磷酸[PI（4，5）P2]控制动物细胞中质膜（PM）功能的所有方面，从其选择性渗透性到细胞骨架的附着。尽管PI（4，5）P2的破坏与多种疾病相关，但仍不清楚细胞如何感知和维持PI（4，5）P2水平以支持各种细胞功能。在这里，我们表明，PIP 4K家族的酶，合成PI（4，5）P2通过一个次要的途径，也作为传感器的紧张PI（4，5）P2水平。PIP 4K通过升高的PI（4，5）P2水平被募集到PM，其中它们抑制主要的PI（4，5）P2合成PIP 5 K。这种简单的稳态机制的扰动揭示了PI（4，5）P2依赖性信号传导对升高的PI（4，5）P2水平的不同敏感性。这些发现揭示了PI（4，5）P2驱动功能的子集可能驱动与破坏PI（4，5）P2稳态相关的疾病。总结：酶PIP 4K通过密切相关的PIP 5 K酶作为PI（4，5）P2合成的传感器和负调节剂，调节许多膜功能的活性。
The lipid molecule phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] controls all aspects of plasma membrane (PM) function in animal cells, from its selective permeability to the attachment of the cytoskeleton. Although disruption of PI(4,5)P2 is associated with a wide range of diseases, it remains unclear how cells sense and maintain PI(4,5)P2 levels to support various cell functions. Here, we show that the PIP4K family of enzymes, which synthesize PI(4,5)P2 via a minor pathway, also function as sensors of tonic PI(4,5)P2 levels. PIP4Ks are recruited to the PM by elevated PI(4,5)P2 levels, where they inhibit the major PI(4,5)P2-synthesizing PIP5Ks. Perturbation of this simple homeostatic mechanism reveals differential sensitivity of PI(4,5)P2-dependent signaling to elevated PI(4,5)P2 levels. These findings reveal that a subset of PI(4,5)P2-driven functions might drive disease associated with disrupted PI(4,5)P2 homeostasis. Summary: The enzyme PIP4K functions as both a sensor and a negative regulator of PI(4,5)P2 synthesis by the closely related PIP5K enzymes, tuning the activity of numerous membrane functions.