The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes

Kay Oliver Schink (), Kia Wee Tan, Hélène Spangenberg, Domenica Martorana, Marte Sneeggen, Virginie Stévenin, Jost Enninga, Coen Campsteijn, Camilla Raiborg and Harald Stenmark ()
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Kay Oliver Schink: University of Oslo, Montebello
Kia Wee Tan: University of Oslo, Montebello
Hélène Spangenberg: University of Oslo, Montebello
Domenica Martorana: University of Oslo, Montebello
Marte Sneeggen: University of Oslo, Montebello
Virginie Stévenin: Leiden University Medical Center
Jost Enninga: Institut Pasteur, Dynamics of Host-Pathogen Interactions Unit
Coen Campsteijn: Institute of Basic Medical Sciences, University of Oslo
Camilla Raiborg: University of Oslo, Montebello
Harald Stenmark: University of Oslo, Montebello

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Uptake of large volumes of extracellular fluid by actin-dependent macropinocytosis has an important role in infection, immunity and cancer development. A key question is how actin assembly and disassembly are coordinated around macropinosomes to allow them to form and subsequently pass through the dense actin network underlying the plasma membrane to move towards the cell center for maturation. Here we show that the PH and FYVE domain protein Phafin2 is recruited transiently to newly-formed macropinosomes by a mechanism that involves coincidence detection of PtdIns3P and PtdIns4P. Phafin2 also interacts with actin via its PH domain, and recruitment of Phafin2 coincides with actin reorganization around nascent macropinosomes. Moreover, forced relocalization of Phafin2 to the plasma membrane causes rearrangement of the subcortical actin cytoskeleton. Depletion of Phafin2 inhibits macropinosome internalization and maturation and prevents KRAS-transformed cancer cells from utilizing extracellular protein as an amino acid source. We conclude that Phafin2 promotes macropinocytosis by controlling timely delamination of actin from nascent macropinosomes for their navigation through the dense subcortical actin network.

Date: 2021
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DOI: 10.1038/s41467-021-26775-x

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