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18.09.17 Building actin filaments using phosphoinositide lipids and high membrane curvature

last modified Sep 20, 2017 10:46 AM
In this JCB article the Gallop lab and colleagues use advanced fluorescence microscopy to follow the biochemistry of actin polymerisation on membranes
18.09.17 Building actin filaments using phosphoinositide lipids and high membrane curvature

Microscopy assay of actin comet tail formation on liposomes

Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature

Daste F et al. (2017) Journal of Cell Biology September 18. DOI: 10.1083/jcb.201704061


Abstract from the paper

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization.

At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42guanosine triphosphate and SNX9 activate N-WASP–WIP- and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P2, and PI(3)P signals are needed for SNX9 assembly via its PX–BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification.

We show that the SNX9-driven actin comets that arise on human disease–associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3)P production, suggesting PI(3)P kinase inhibitors as a therapeutic strategy in Lowe syndrome.


Read more about research in the Gallop lab.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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