Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 7, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2119286119
Keywords
phosphatidylserine; XKR scramblase; cell death; regulatory T cells
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Funding
- Japan Society for the Promotion of Science [21H04770]
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XK and VPS13A are essential for the exposure of phosphatidylserine mediated by P2X7 receptor in T cells, with XK located on the plasma membrane and VPS13A acting as a lipid transporter in the cytoplasm. Blue-native polyacrylamide gel electrophoresis showed that XK and VPS13A interact at the membrane, indicating their role in maintaining homeostasis in the immune and nerve systems.
A high extracellular adenosine triphosphate (ATP) concentration rapidly and reversibly exposes phosphatidylserine (PtdSer) in T cells by binding to the P2X7 receptor, which ultimately leads to necrosis. Using mouse T cell transformants expressing P2X7, we herein performed CRISPR/Cas9 screening for the molecules responsible for P2X7-mediated PtdSer exposure. In addition to Eros, which is required for the localization of P2X7 to the plasma membrane, this screening identified Xk and Vps13a as essential components for this process. Xk is present at the plasma membrane, and its paralogue, Xkr8, functions as a phospholipid scramblase. Vps13a is a lipid transporter in the cytoplasm. Blue-native polyacrylamide gel electrophoresis indicated that Xk and Vps13a interacted at the membrane. A null mutation in Xk or Vps13a blocked P2X7-mediated PtdSer exposure, the internalization of phosphatidylcholine, and cytolysis. Xk and Vps13a formed a complex in mouse splenic T cells, and Xk was crucial for ATP-induced PtdSer exposure and cytolysis in CD25(+)CD4(+) T cells. XK and VPS13A are responsible for McLeod syndrome and chorea-acanthocytosis, both characterized by a progressive movement disorder and cognitive and behavior changes. Our results suggest that the phospholipid scrambling activity mediated by XK and VPS13A is essential for maintaining homeostasis in the immune and nerve systems.
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