Arf6 controls retromer traffic and intracellular cholesterol distribution via a phosphoinositide-based mechanism

Catherine Marquer (), Huasong Tian, Julie Yi, Jayson Bastien, Claudia Dall'Armi, YoungJoo Yang-Klingler, Bowen Zhou, Robin Barry Chan and Gilbert Di Paolo ()
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Catherine Marquer: Columbia University Medical Center
Huasong Tian: Columbia University Medical Center
Julie Yi: Columbia University Medical Center
Jayson Bastien: Columbia University Medical Center
Claudia Dall'Armi: Columbia University Medical Center
YoungJoo Yang-Klingler: Columbia University Medical Center
Bowen Zhou: Columbia University Medical Center
Robin Barry Chan: Columbia University Medical Center
Gilbert Di Paolo: Columbia University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Small GTPases play a critical role in membrane traffic. Among them, Arf6 mediates transport to and from the plasma membrane, as well as phosphoinositide signalling and cholesterol homeostasis. Here we delineate the molecular basis for the link between Arf6 and cholesterol homeostasis using an inducible knockout (KO) model of mouse embryonic fibroblasts (MEFs). We find that accumulation of free cholesterol in the late endosomes/lysosomes of Arf6 KO MEFs results from mistrafficking of Niemann–Pick type C protein NPC2, a cargo of the cation-independent mannose-6-phosphate receptor (CI-M6PR). This is caused by a selective increase in an endosomal pool of phosphatidylinositol-4-phosphate (PI4P) and a perturbation of retromer, which controls the retrograde transport of CI-M6PR via sorting nexins, including the PI4P effector SNX6. Finally, reducing PI4P levels in KO MEFs through independent mechanisms rescues aberrant retromer tubulation and cholesterol mistrafficking. Our study highlights a phosphoinositide-based mechanism for control of cholesterol distribution via retromer.

Date: 2016
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DOI: 10.1038/ncomms11919

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