Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
Curr Opin Cell Biol. 2022 Jun;76:102086. doi: 10.1016/j.ceb.2022.102086. Epub 2022 May 16.
Phosphoinositide signaling lipids are crucial for eukaryotes and regulate many aspects of cell function. These signaling molecules are difficult to study because they are extremely low abundance. Here, we focus on two of the lowest abundance phosphoinositides, PI(3,5)P and PI(5)P, which play critical roles in cellular homeostasis, membrane trafficking and transcription. Their levels are tightly regulated by a protein complex that includes PIKfyve, Fig4 and Vac14. Importantly, mutations in this complex that decrease PI(3,5)P and PI(5)P are linked to human diseases, especially those of the nervous system. Paradoxically, PIKfyve inhibitors which decrease PI(3,5)P and PI(5)P, are currently being tested for some neurodegenerative diseases, as well as other diverse diseases including some cancers, and as a treatment for SARS-CoV2 infection. A more comprehensive picture of the pathways that are regulated by PIKfyve will be critical to understand the roles of PI(3,5)P and PI(5)P in normal human physiology and in disease.
磷酸肌醇信号脂质对真核生物至关重要，调节细胞功能的许多方面。这些信号分子很难研究，因为它们的丰度极低。在这里，我们专注于两种丰度最低的磷酸肌醇，PI(3,5)P 和 PI(5)P，它们在细胞内稳态、膜运输和转录中发挥关键作用。它们的水平受到包括 PIKfyve、Fig4 和 Vac14 在内的蛋白质复合物的严格调节。重要的是，该复合物中导致 PI(3,5)P 和 PI(5)P 减少的突变与人类疾病有关，尤其是神经系统疾病。矛盾的是，目前正在针对一些神经退行性疾病以及其他多种疾病（包括一些癌症）以及 SARS-CoV2 感染的治疗，测试 PIKfyve 抑制剂来降低 PI(3,5)P 和 PI(5)P。更全面地了解 PIKfyve 调节的途径对于理解 PI(3,5)P 和 PI(5)P 在正常人体生理学和疾病中的作用至关重要。
