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J Cell Biol 2017 Nov 06;21611:3745-3765. doi: 10.1083/jcb.201704061.
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Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature.

Daste F , Walrant A , Holst MR , Gadsby JR , Mason J , Lee JE , Brook D , Mettlen M , Larsson E , Lee SF , Lundmark R , Gallop JL .

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 Cdc42⋅guanosine 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.

PubMed ID: 28923975
PMC ID: PMC5674896
Article link: J Cell Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: actb anxa7 cdc42 clta cltc crygdl2.2 inpp4a ocrl rpe snx9 tf was wipf2
GO keywords: actin filament polymerization [+]

Disease Ontology terms: oculocerebrorenal syndrome

Article Images: [+] show captions
References [+] :
Aghamohammadzadeh, Differential requirements for actin during yeast and mammalian endocytosis. 2009, Pubmed