Phosphatidylserine Externalization, "necroptotic Bodies" Release, and Phagocytosis During Necroptosis

Overview

Journal PLoS Biol

Specialty Biology

Date 2017 Jun 27

PMID 28650960

Citations 104

Authors

Sefi Zargarian

Inbar Shlomovitz

Ziv Erlich

Aria Hourizadeh

Yifat Ofir-Birin

Ben A Croker

Neta Regev-Rudzki

Liat Edry-Botzer

Motti Gerlic

Affiliations

Soon will be listed here.

Abstract

Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the "find me" and "eat me" signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such "eat me" signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific "find me" and "eat me" signals.

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References

Kaiser W, Daley-Bauer L, Thapa R, Mandal P, Berger S, Huang C . RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci U S A. 2014; 111(21):7753-8. PMC: 4040608. DOI: 10.1073/pnas.1401857111. View

Dillon C, Weinlich R, Rodriguez D, Cripps J, Quarato G, Gurung P . RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014; 157(5):1189-202. PMC: 4068710. DOI: 10.1016/j.cell.2014.04.018. View

Segawa K, Nagata S . An Apoptotic 'Eat Me' Signal: Phosphatidylserine Exposure. Trends Cell Biol. 2015; 25(11):639-650. DOI: 10.1016/j.tcb.2015.08.003. View

Sun L, Wang H, Wang Z, He S, Chen S, Liao D . Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012; 148(1-2):213-27. DOI: 10.1016/j.cell.2011.11.031. View

Krysko D, Vanden Berghe T, DHerde K, Vandenabeele P . Apoptosis and necrosis: detection, discrimination and phagocytosis. Methods. 2008; 44(3):205-21. DOI: 10.1016/j.ymeth.2007.12.001. View

Galluzzi L, Bravo-San Pedro J, Vitale I, Aaronson S, Abrams J, Adam D . Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2014; 22(1):58-73. PMC: 4262782. DOI: 10.1038/cdd.2014.137. View

Kaczmarek A, Vandenabeele P, Krysko D . Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013; 38(2):209-23. DOI: 10.1016/j.immuni.2013.02.003. View

Denecker G, Vercammen D, Steemans M, Vanden Berghe T, Brouckaert G, van Loo G . Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria. Cell Death Differ. 2001; 8(8):829-40. DOI: 10.1038/sj.cdd.4400883. View

Kim Y, Chen J, Langen R, Chan J . Monitoring apoptosis and neuronal degeneration by real-time detection of phosphatidylserine externalization using a polarity-sensitive indicator of viability and apoptosis. Nat Protoc. 2010; 5(8):1396-405. PMC: 4340478. DOI: 10.1038/nprot.2010.101. View

10.

Cullen S, Henry C, Kearney C, Logue S, Feoktistova M, Tynan G . Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. 2013; 49(6):1034-48. DOI: 10.1016/j.molcel.2013.01.025. View

11.

Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S . Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2001; 1(6):489-95. DOI: 10.1038/82732. View

12.

KERR J, Wyllie A, Currie A . Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972; 26(4):239-57. PMC: 2008650. DOI: 10.1038/bjc.1972.33. View

13.

Ferraro-Peyret C, Quemeneur L, Flacher M, Revillard J, Genestier L . Caspase-independent phosphatidylserine exposure during apoptosis of primary T lymphocytes. J Immunol. 2002; 169(9):4805-10. DOI: 10.4049/jimmunol.169.9.4805. View

14.

Upton J, Kaiser W, Mocarski E . DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe. 2012; 11(3):290-7. PMC: 3531981. DOI: 10.1016/j.chom.2012.01.016. View

15.

Sawai H, Domae N . Discrimination between primary necrosis and apoptosis by necrostatin-1 in Annexin V-positive/propidium iodide-negative cells. Biochem Biophys Res Commun. 2011; 411(3):569-73. DOI: 10.1016/j.bbrc.2011.06.186. View

16.

Wallach D, Kang T, Kovalenko A . Concepts of tissue injury and cell death in inflammation: a historical perspective. Nat Rev Immunol. 2013; 14(1):51-9. DOI: 10.1038/nri3561. View

17.

Atkin-Smith G, Paone S, Zanker D, Duan M, Phan T, Chen W . Isolation of cell type-specific apoptotic bodies by fluorescence-activated cell sorting. Sci Rep. 2017; 7:39846. PMC: 5216387. DOI: 10.1038/srep39846. View

18.

van Loo G, Demol H, van Gurp M, Hoorelbeke B, Schotte P, Beyaert R . A matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) analysis of proteins released from isolated liver mitochondria treated with recombinant truncated Bid. Cell Death Differ. 2002; 9(3):301-8. DOI: 10.1038/sj.cdd.4400966. View

19.

Gerlic M, Horowitz J, Horowitz S . Mycoplasma fermentans inhibits tumor necrosis factor alpha-induced apoptosis in the human myelomonocytic U937 cell line. Cell Death Differ. 2004; 11(11):1204-12. DOI: 10.1038/sj.cdd.4401482. View

20.

Regev-Rudzki N, Wilson D, Carvalho T, Sisquella X, Coleman B, Rug M . Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell. 2013; 153(5):1120-33. DOI: 10.1016/j.cell.2013.04.029. View