The Phosphoinositide Coincidence Detector Phafin2 Promotes Macropinocytosis by Coordinating Actin Organisation at Forming Macropinosomes

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Nov 13

PMID 34772942

Citations 11

Authors

Kay Oliver Schink

Kia Wee Tan

Helene Spangenberg

Domenica Martorana

Marte Sneeggen

Virginie Stevenin

Jost Enninga

Coen Campsteijn

Camilla Raiborg

Harald Stenmark

Affiliations

Soon will be listed here.

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.

Citing Articles

Cellular Regulation of Macropinocytosis.

Wu Y, Hu X, Wei Z, Lin Q Int J Mol Sci. 2024; 25(13).

PMID: 39000072 PMC: 11241348. DOI: 10.3390/ijms25136963.

The role of Phafin proteins in cell signaling pathways and diseases.

Tang T, Sun J, Li C Open Life Sci. 2024; 19(1):20220896.

PMID: 38947768 PMC: 11211877. DOI: 10.1515/biol-2022-0896.

Leep2A and Leep2B function as a RasGAP complex to regulate macropinosome formation.

Chao X, Yang Y, Gong W, Zou S, Tu H, Li D J Cell Biol. 2024; 223(9).

PMID: 38888895 PMC: 11187982. DOI: 10.1083/jcb.202401110.

Contrasting effects of filamin A and B proteins in modulating filovirus entry.

Shepley-McTaggart A, Liang J, Ding Y, Djurkovic M, Kriachun V, Shtanko O PLoS Pathog. 2023; 19(8):e1011595.

PMID: 37585478 PMC: 10461817. DOI: 10.1371/journal.ppat.1011595.

Phafins Are More Than Phosphoinositide-Binding Proteins.

Tang T, Hasan M, Capelluto D Int J Mol Sci. 2023; 24(9).

PMID: 37175801 PMC: 10178739. DOI: 10.3390/ijms24098096.

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