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Suicidal Membrane Repair Regulates Phosphatidylserine Externalization during Apoptosis

J. Biol. Chem., 21 August 2009
Vol. 284, Issue 34, p. 22512-22516
DOI: 10.1074/jbc.C109.022913

Suicidal Membrane Repair Regulates Phosphatidylserine Externalization during Apoptosis

  1. Banafsheh Mirnikjoo,
  2. Krishnakumar Balasubramanian and
  3. Alan J. Schroit1
  1. From the Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
  1. 1 To whom correspondence should be addressed: M. D. Anderson Cancer Center, Dept. of Cancer Biology, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-8586; Fax: 713-792-8747; E-mail: aschroit{at}mdanderson.org.

Abstract

One of the hallmarks of apoptosis is the redistribution of phosphatidylserine (PS) from the inner-to-outer plasma membrane (PM) leaflet, where it functions as a ligand for phagocyte recognition and the suppression of inflammatory responses. The mechanism by which apoptotic cells externalize PS has been assumed to involve “scramblases” that randomize phospholipids across the PM bilayer. These putative activities, however, have not been unequivocally proven to be responsible for the redistribution of lipids. Because elevated cytosolic Ca2+ is critical to this process and is also required for activation of lysosome-PM fusion during membrane repair, we hypothesized that apoptosis could activate a “pseudo”-membrane repair response that results in the fusion of lysosomes with the PM. Using a membrane-specific probe that labels endosomes and lysosomes and fluorescein-labeled annexin 5 that labels PS, we show that the appearance of PS at the cell surface during apoptosis is dependent on the fusion of lysosomes with the PM, a process that is inhibited with the lysosomotrophe, chloroquine. We demonstrate that apoptotic cells evoke a persistent pseudo-membrane repair response that likely redistributes lysosomal-derived PS to the PM outer leaflet that leads to membrane expansion and the formation of apoptotic blebs. Our data suggest that inhibition of lysosome-PM fusion-dependent redistribution of PS that occurs as a result of chemotherapy- and radiotherapy-induced apoptosis will prevent PS-dependent anti-inflammatory responses that preclude the development of tumor- and patient-specific immune responses.

Footnotes

  • * This work was supported, in whole or in part, by National Institutes of Health Grant CA98527 (to A. J. S.). This work was also supported by Department of Defense Grant BCRPW81XWH-06-1-0347 (to B. M.) and a grant from the John Q. Gaines Foundation.

  • This article was selected as a Paper of the Week.

  • Received May 20, 2009.
  • Revision received June 14, 2009.

Citation:

B. Mirnikjoo, K. Balasubramanian, and A. J. Schroit, Suicidal Membrane Repair Regulates Phosphatidylserine Externalization during Apoptosis. J. Biol. Chem. 284, 22512-22516 (2009).

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