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一种新的体内平衡机制调节质膜上 PI(4,5)P2 依赖性信号转导。

A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane.

机构信息

Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.

出版信息

J Cell Sci. 2023 Aug 15;136(16). doi: 10.1242/jcs.261494. Epub 2023 Aug 29.

DOI:10.1242/jcs.261494
PMID:37534432
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10482388/
Abstract

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.

摘要

脂质分子磷脂酰肌醇（4,5）-二磷酸[PI（4,5）P2]控制动物细胞质膜（PM）功能的各个方面，从其选择性通透性到细胞骨架的附着。尽管 PI（4,5）P2 的破坏与广泛的疾病有关，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，通过次要途径合成 PI（4,5）P2 的 PIP4K 酶家族也作为 PI（4,5）P2 水平的张力传感器发挥作用。PIP4Ks 被募集到 PM 是由于 PI（4,5）P2 水平升高，在那里它们抑制主要的 PI（4,5）P2 合成 PIP5Ks。这种简单的动态平衡机制的破坏揭示了 PI（4,5）P2 依赖性信号对升高的 PI（4,5）P2 水平的不同敏感性。这些发现表明，PI（4,5）P2 驱动的功能子集可能导致与 PI（4,5）P2 动态平衡破坏相关的疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/4c9cfb4a986b/joces-136-261494-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/af6ecce59137/joces-136-261494-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/37900d13ed7c/joces-136-261494-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/2ae39d0888bf/joces-136-261494-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/0bfea6a62cd2/joces-136-261494-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/5befe22d4173/joces-136-261494-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/a7237872b6fb/joces-136-261494-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/e0056f88c636/joces-136-261494-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/4c9cfb4a986b/joces-136-261494-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/af6ecce59137/joces-136-261494-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/37900d13ed7c/joces-136-261494-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/2ae39d0888bf/joces-136-261494-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/0bfea6a62cd2/joces-136-261494-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/5befe22d4173/joces-136-261494-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/a7237872b6fb/joces-136-261494-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/e0056f88c636/joces-136-261494-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0397/10482388/4c9cfb4a986b/joces-136-261494-g8.jpg

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