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

Author

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  • Kay Oliver Schink

    (University of Oslo, Montebello
    Institute for Cancer Research, Oslo University Hospital, Montebello)

  • Kia Wee Tan

    (University of Oslo, Montebello
    Institute for Cancer Research, Oslo University Hospital, Montebello)

  • Hélène Spangenberg

    (University of Oslo, Montebello
    Institute for Cancer Research, Oslo University Hospital, Montebello)

  • Domenica Martorana

    (University of Oslo, Montebello
    Institute for Cancer Research, Oslo University Hospital, Montebello)

  • Marte Sneeggen

    (University of Oslo, Montebello
    Institute for Cancer Research, Oslo University Hospital, Montebello)

  • Virginie Stévenin

    (Leiden University Medical Center
    Institut Pasteur, Dynamics of Host-Pathogen Interactions Unit)

  • 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
    Institute for Cancer Research, Oslo University Hospital, Montebello)

  • Harald Stenmark

    (University of Oslo, Montebello
    Institute for Cancer Research, Oslo University Hospital, Montebello)

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.

Suggested Citation

  • Kay Oliver Schink & Kia Wee Tan & Hélène Spangenberg & Domenica Martorana & Marte Sneeggen & Virginie Stévenin & Jost Enninga & Coen Campsteijn & Camilla Raiborg & Harald Stenmark, 2021. "The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26775-x
    DOI: 10.1038/s41467-021-26775-x
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    References listed on IDEAS

    as
    1. Kangmin He & Robert Marsland III & Srigokul Upadhyayula & Eli Song & Song Dang & Benjamin R. Capraro & Weiming Wang & Wesley Skillern & Raphael Gaudin & Minghe Ma & Tom Kirchhausen, 2017. "Dynamics of phosphoinositide conversion in clathrin-mediated endocytic traffic," Nature, Nature, vol. 552(7685), pages 410-414, December.
    2. Marte Sneeggen & Nina Marie Pedersen & Coen Campsteijn & Ellen Margrethe Haugsten & Harald Stenmark & Kay Oliver Schink, 2019. "WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling," Nature Communications, Nature, vol. 10(1), pages 1-20, December.
    3. Craig Ramirez & Andrew D. Hauser & Emily A. Vucic & Dafna Bar-Sagi, 2019. "Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis," Nature, Nature, vol. 576(7787), pages 477-481, December.
    4. Cosimo Commisso & Shawn M. Davidson & Rengin G. Soydaner-Azeloglu & Seth J. Parker & Jurre J. Kamphorst & Sean Hackett & Elda Grabocka & Michel Nofal & Jeffrey A. Drebin & Craig B. Thompson & Joshua D, 2013. "Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells," Nature, Nature, vol. 497(7451), pages 633-637, May.
    5. Sarah R. Barger & Nicholas S. Reilly & Maria S. Shutova & Qingsen Li & Paolo Maiuri & John M. Heddleston & Mark S. Mooseker & Richard A. Flavell & Tatyana Svitkina & Patrick W. Oakes & Mira Krendel & , 2019. "Membrane-cytoskeletal crosstalk mediated by myosin-I regulates adhesion turnover during phagocytosis," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
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