Abstract
ABSTRACTMacropinocytosis allows cells to take up extracellular material in a non-selective manner into large vesicles called macropinosomes. After internalization, macropinosomes acquire phosphatidylinositol 3-phosphate (PtdIns3P) on their limiting membrane as they mature into endosomal-like vesicles. The molecular mechanisms that underlie recycling of membranes and transmembrane proteins from these macropinosomes still need to be defined. Here, we report that JIP4 (officially known as SPAG9), a protein previously described to bind to microtubule motors, is recruited to tubulating subdomains on macropinosomes by the PtdIns3P-binding protein Phafin2 (officially known as PLEKHF2). These JIP4-positive tubulating subdomains on macropinosomes contain F-actin, the retromer recycling complex and the retromer cargo VAMP3. Disruption of the JIP4–Phafin2 interaction, deletion of Phafin2 or inhibition of PtdIns3P production by VPS34 impairs JIP4 recruitment to macropinosomes. Whereas knockout of JIP4 suppresses tubulation, its overexpression enhances tubulation from macropinosomes. JIP4-knockout cells display increased retention of macropinocytic cargo in both early and late macropinosomes. Collectively, these data identify JIP4 and Phafin2 as components of a tubular recycling pathway that operates from macropinosomes.This article has an associated First Person interview with the first author of the paper.
Highlights
Macropinocytosis is a process that enables cells to take up large amounts of extracellular fluid (Swanson and King, 2019)
JIP4 interacts with Phafin2 in vitro We have recently identified the phosphoinositide-binding protein Phafin2 to be a regulator of macropinosome formation (Schink et al, 2017 preprint)
We identified JIP4 as a potential interactor of Phafin2 (Table S1). This was interesting, as JIP4 and its homolog JIP3 had previously been reported to be important for macropinocytosis (Williamson and Donaldson, 2019)
Summary
Macropinocytosis is a process that enables cells to take up large amounts of extracellular fluid (Swanson and King, 2019). This fluid is internalized into large vesicles that are called macropinosomes. During this process, large regions of plasma membrane as well as the proteins within are internalized. Handling Editor: David Stephens Received 29 January 2021; Accepted 27 May 2021 phosphatidylinositol 3-phosphate (PtdIns3P) on their limiting membranes. To preserve the composition of the plasma membrane, it is important that membranes and membrane proteins are recycled from this compartment, and transported back to the cell surface
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