Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Weill Institute for Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
J Cell Sci. 2022 Mar 1;135(5). doi: 10.1242/jcs.259365. Epub 2021 Oct 22.
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα) is the major enzyme responsible for generating phosphatidylinositol (4)-phosphate [PI(4)P] at the plasma membrane. This lipid kinase forms two multicomponent complexes, both including a palmitoylated anchor, EFR3. Whereas both PI4KIIIα complexes support production of PI(4)P, the distinct functions of each complex and mechanisms underlying the interplay between them remain unknown. Here, we present roles for differential palmitoylation patterns within a tri-cysteine motif in EFR3B (Cys5, Cys7 and Cys8) in controlling the distribution of PI4KIIIα between these two complexes at the plasma membrane and corresponding functions in phosphoinositide homeostasis. Spacing of palmitoyl groups within three doubly palmitoylated EFR3B 'lipoforms' affects both interactions between EFR3B and TMEM150A, a transmembrane protein governing formation of a PI4KIIIα complex functioning in rapid phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] resynthesis following phospholipase C signaling, and EFR3B partitioning within liquid-ordered and -disordered regions of the plasma membrane. This work identifies a palmitoylation code involved in controlling protein-protein and protein-lipid interactions that affect a plasma membrane-resident lipid biosynthetic pathway.
磷脂酰肌醇 4-激酶 IIIα（PI4KIIIα）是在质膜处生成磷脂酰肌醇（4）-磷酸[PI（4）P]的主要酶。这种脂质激酶形成两个多成分复合物，都包括一个棕榈酰化的锚，EFR3。虽然两个 PI4KIIIα 复合物都支持 PI（4）P 的产生，但每个复合物的独特功能以及它们之间相互作用的机制仍不清楚。在这里，我们介绍了 EFR3B（Cys5、Cys7 和 Cys8）三半胱氨酸基序内的差异棕榈酰化模式在控制 PI4KIIIα在质膜处两种复合物之间分布以及在磷酸肌醇稳态中的相应功能中的作用。三个双棕榈酰化 EFR3B“脂型”内的棕榈酰基间隔影响 EFR3B 与 TMEM150A 之间的相互作用，TMEM150A 是一种跨膜蛋白，控制形成 PI4KIIIα 复合物，该复合物在 PLC 信号后快速合成磷脂酰肌醇（4,5）-双磷酸[PI（4,5）P2]，以及 EFR3B 在质膜有序区和无序区的分配。这项工作确定了一个参与控制蛋白质-蛋白质和蛋白质-脂质相互作用的棕榈酰化密码，这些相互作用影响质膜驻留的脂质生物合成途径。
