Requirement of Xk and Vps13a for the P2X7-mediated phospholipid scrambling and cell lysis in mouse T cells.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Amino Acid Transport Systems, Neutral/*metabolism ; Phospholipids/*metabolism ; Receptors, Purinergic P2X7/*metabolism ; T-Lymphocytes/*physiology ; Vesicular Transport Proteins/*metabolism; Adenosine Triphosphate ; Amino Acid Transport Systems, Neutral/genetics ; Animals ; CRISPR-Cas Systems ; Cell Death ; Cell Line ; Gene Deletion ; Gene Expression Regulation/drug effects ; Genome-Wide Association Study ; HEK293 Cells ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Phosphatidylserines/pharmacology ; Receptors, Purinergic P2X7/genetics ; Vesicular Transport Proteins/genetics
    • Abstract:
      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.
      Competing Interests: Competing interest statement: Y.R. is on a leave of absence from Otsuka Pharmaceutical Co. S.N. is one of the co-authors of a review article on cell death published in January 2018 [L. Galluzzi et al., Cell Death Differ. 25, 486–541 (2018)], of which two of the referees were co-authors.
      (Copyright © 2022 the Author(s). Published by PNAS.)
    • References:
      J Mol Biol. 2002 Apr 5;317(4):591-600. (PMID: 11955011)
      Front Physiol. 2016 Jul 08;7:275. (PMID: 27458383)
      Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Oct;1866(10):159003. (PMID: 34216812)
      Anal Biochem. 2009 Oct 1;393(1):129-31. (PMID: 19523435)
      Immunity. 2017 Jul 18;47(1):15-31. (PMID: 28723547)
      Nat Rev Immunol. 2007 Nov;7(11):875-88. (PMID: 17948021)
      Nature. 2021 Mar;591(7848):131-136. (PMID: 33472215)
      Purinergic Signal. 2013 Sep;9(3):285-306. (PMID: 23404828)
      Mol Biol Cell. 2020 Oct 15;31(22):2425-2436. (PMID: 32845802)
      Nature. 1989 Dec 21-28;342(6252):877-83. (PMID: 2687698)
      Front Immunol. 2020 Jun 10;11:1179. (PMID: 32587592)
      Neurol Genet. 2019 Apr 22;5(3):e328. (PMID: 31086825)
      Cell Death Differ. 2016 Jun;23(6):952-61. (PMID: 26891692)
      Nat Genet. 2001 Jun;28(2):119-20. (PMID: 11381253)
      Nat Struct Mol Biol. 2021 Oct;28(10):825-834. (PMID: 34625749)
      J Immunol. 2009 Mar 1;182(5):2898-908. (PMID: 19234185)
      Science. 2014 Jan 3;343(6166):84-87. (PMID: 24336571)
      Biochim Biophys Acta. 2000 Jun 15;1501(2-3):99-115. (PMID: 10838184)
      J Physiol. 1999 Sep 1;519 Pt 2:335-46. (PMID: 10457053)
      PLoS One. 2008 Jul 09;3(7):e2599. (PMID: 18612415)
      J Immunol. 2005 Sep 1;175(5):3075-83. (PMID: 16116196)
      Curr Opin Struct Biol. 1997 Aug;7(4):457-62. (PMID: 9266165)
      J Immunol. 2008 Jan 1;180(1):300-8. (PMID: 18097031)
      Physiol Rev. 2016 Apr;96(2):605-45. (PMID: 26936867)
      Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19246-51. (PMID: 22084121)
      Biochim Biophys Acta. 2010 Sep;1798(9):1797-804. (PMID: 20529664)
      Proc Natl Acad Sci U S A. 1971 Oct;68(10):2564-8. (PMID: 4332815)
      Nat Chem Biol. 2020 Dec;16(12):1321-1330. (PMID: 33199908)
      Elife. 2019 Feb 11;8:. (PMID: 30741634)
      Nature. 2010 Dec 9;468(7325):834-8. (PMID: 21107324)
      Cell Death Differ. 1998 Mar;5(3):191-9. (PMID: 10200464)
      Science. 2013 Jul 26;341(6144):403-6. (PMID: 23845944)
      J Biol Chem. 2005 Oct 7;280(40):33968-76. (PMID: 15994333)
      J Cell Biol. 2018 Oct 1;217(10):3625-3639. (PMID: 30093493)
      Cell. 1994 Jun 17;77(6):869-80. (PMID: 8004674)
      Annu Rev Physiol. 2019 Feb 10;81:43-62. (PMID: 30354932)
      Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
      Cell. 2019 Oct 17;179(3):659-670.e13. (PMID: 31587896)
      J Immunol. 2020 Feb 1;204(3):559-568. (PMID: 31862710)
      Blood. 1993 May 15;81(10):2804-9. (PMID: 7683930)
      J Biol Chem. 2004 May 21;279(21):21815-23. (PMID: 14996828)
      Nat Rev Cancer. 2018 Oct;18(10):601-618. (PMID: 30006588)
      Pancreas. 2018 May/Jun;47(5):643-651. (PMID: 29683976)
      Annu Rev Immunol. 2019 Apr 26;37:325-347. (PMID: 30676821)
      Physiol Rev. 2002 Oct;82(4):1013-67. (PMID: 12270951)
      Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12800-5. (PMID: 26417084)
      J Biol Chem. 2003 Mar 7;278(10):8853-60. (PMID: 12496266)
      Nat Genet. 2001 Jun;28(2):121-2. (PMID: 11381254)
      Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9509-14. (PMID: 27503893)
      J Immunol. 2007 Aug 1;179(3):1913-25. (PMID: 17641058)
      Nat Chem Biol. 2020 Jun;16(6):644-652. (PMID: 32367017)
      EMBO J. 2006 Nov 1;25(21):5071-82. (PMID: 17036048)
      J Cell Biol. 2007 Jan 29;176(3):283-94. (PMID: 17261847)
      Blood. 2006 Dec 15;108(13):4094-101. (PMID: 16912227)
      Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2907-2912. (PMID: 30718401)
      Science. 2014 Jun 6;344(6188):1164-8. (PMID: 24904167)
      Biomed J. 2019 Jun;42(3):141-154. (PMID: 31466708)
      J Biol Chem. 1998 May 29;273(22):13950-6. (PMID: 9593744)
      J Biol Chem. 2014 Oct 31;289(44):30257-30267. (PMID: 25231987)
      Sci Signal. 2011 Mar 01;4(162):ra12. (PMID: 21364186)
      Mol Biol Cell. 2003 Jul;14(7):2655-64. (PMID: 12857854)
      Nature. 2014 Dec 11;516(7530):207-12. (PMID: 25383531)
      Cell Death Differ. 2018 Mar;25(3):486-541. (PMID: 29362479)
      Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1183-1194. (PMID: 28286160)
      Immunity. 2001 Nov;15(5):825-35. (PMID: 11728343)
      Sci Rep. 2016 Dec 21;6:39618. (PMID: 28000761)
    • Contributed Indexing:
      Keywords: P2X7 receptor; XKR scramblase; cell death; phosphatidylserine; regulatory T cells
    • Accession Number:
      0 (Amino Acid Transport Systems, Neutral)
      0 (P2rx7 protein, mouse)
      0 (Phosphatidylserines)
      0 (Phospholipids)
      0 (Receptors, Purinergic P2X7)
      0 (Vesicular Transport Proteins)
      0 (Vps13a protein, mouse)
      0 (Xkh protein, mouse)
      8L70Q75FXE (Adenosine Triphosphate)
    • Publication Date:
      Date Created: 20220210 Date Completed: 20220310 Latest Revision: 20220310
    • Publication Date:
      20240829
    • Accession Number:
      PMC8851519
    • Accession Number:
      10.1073/pnas.2119286119
    • Accession Number:
      35140185