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J Cell Biol. 2017 Nov 6;216(11):3745-3765. doi: 10.1083/jcb.201704061. Epub 2017 Sep 18.

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

Author information

1
Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK.
2
Integrative Medical Biology, Umeå University, Umeå, Sweden.
3
Department of Chemistry, University of Cambridge, Cambridge, England, UK.
4
University of Texas Southwestern Medical Center, Dallas, TX.
5
Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK j.gallop@gurdon.cam.ac.uk.

Abstract

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.

PMID:
28923975
PMCID:
PMC5674896
DOI:
10.1083/jcb.201704061
[Indexed for MEDLINE]
Free PMC Article

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