2026-05-18 東京大学
PLDが制御する膜上の分子拡散と細胞の極性形成
＜関連情報＞
- https://www.c.u-tokyo.ac.jp/info/news/topics/20260518140000.html
- https://www.pnas.org/doi/10.1073/pnas.2608790123
ホスホリパーゼDはミリストイル化タンパク質の膜上拡散性を調節し、PIP3パッチ領域を規定する Phospholipase D regulates on-membrane diffusivity of a myristoylated protein and defines the PIP3 patch territory
Gen Honda, Chihuku Tanaka, Hidenori Hashimura, +4 , and Miho Yanagisawa
Proceedings of the National Academy of Sciences Published:May 13, 2026
DOI:https://doi.org/10.1073/pnas.2608790123
Significance
In living cells, biochemical reactions are often confined to subregions in the membrane, facilitating local occurrences of specific signals that regulate membrane protrusion, internalization, fusion, and fission. This is puzzling from a physics perspective because a lipid membrane should allow molecules to spread out freely given its two-dimensional fluidic nature. Herein, we found that the fluidity of artificial membranes becomes markedly reduced by cytosolic extracts and that it can be mimicked by lipid-modifying protein phospholipase D (PLD). In real cells too, PLD regulates the diffusion of membrane proteins. These results suggest that PLD, apart from its well-known role in generating lipid second messengers, is a key regulator of molecular diffusion impacting spatial clustering of actin-regulating signals.
Abstract
In living cells, the control of molecular diffusion is pivotal for highly fluidic membranes to serve as substrates for biochemical reactions and cytoskeletal assemblies. Lateral diffusion in membranes depends on a highly diverse and homeostatically controlled lipid composition. This complexity has limited our understanding of how diffusivity in biological membranes is regulated. In this study, we show that lipid diffusion in model membranes decreases markedly in the presence of cytosolic extracts. The reduction in lipid diffusivity can be pharmacologically inhibited by targeting phospholipase D (PLD). Conversely, lipid diffusivity was reduced when PLD alone was added to the membrane. Phosphatidic acid (PA), a direct product of PLD, diffuses slowly, and its presence reduces the diffusivity of surrounding lipids. Furthermore, we found that PLD controls the lateral diffusion of a myristoylated protein PKBR1 in Dictyostelium cells, possibly through auxiliary electrostatic interactions between cationic residues located near the lipidated tail and anionic phospholipids. In line with the role of PKBR1 in regulating phosphatidylinositol(3,4,5)-trisphosphates (PIP3), PLD overexpression suppressed the size and lifetime of PIP3 microdomains as well as the sensitivity of GPCR-mediated PIP3 elevation. Our results underscore the importance of PLD and its product PA as regulators of lipidated protein diffusivity, facilitating the dynamical lateral organization of phosphoinositides in the plasma membrane.
