Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.

Natural killer (NK) cells kill a target cell by secreting perforin into the lytic immunological synapse, a specialized interface formed between the NK cell and its target. Perforin creates pores in target cell membranes allowing delivery of proapoptotic enzymes. Despite the fact that secreted perfor...

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Autores principales:	Yu Li, Jordan S Orange
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c15feb9cd1be4103b9d07e6b8758bbb8
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spelling	oai:doaj.org-article:c15feb9cd1be4103b9d07e6b8758bbb82021-12-02T19:54:41ZDegranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.1544-91731545-788510.1371/journal.pbio.3001328https://doaj.org/article/c15feb9cd1be4103b9d07e6b8758bbb82021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001328https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Natural killer (NK) cells kill a target cell by secreting perforin into the lytic immunological synapse, a specialized interface formed between the NK cell and its target. Perforin creates pores in target cell membranes allowing delivery of proapoptotic enzymes. Despite the fact that secreted perforin is in close range to both the NK and target cell membranes, the NK cell typically survives while the target cell does not. How NK cells preferentially avoid death during the secretion of perforin via the degranulation of their perforin-containing organelles (lytic granules) is perplexing. Here, we demonstrate that NK cells are protected from perforin-mediated autolysis by densely packed and highly ordered presynaptic lipid membranes, which increase packing upon synapse formation. When treated with 7-ketocholesterol, lipid packing is reduced in NK cells making them susceptible to perforin-mediated lysis after degranulation. Using high-resolution imaging and lipidomics, we identified lytic granules themselves as having endogenously densely packed lipid membranes. During degranulation, lytic granule-cell membrane fusion thereby further augments presynaptic membrane packing, enhancing membrane protection at the specific sites where NK cells would face maximum concentrations of secreted perforin. Additionally, we found that an aggressive breast cancer cell line is perforin resistant and evades NK cell-mediated killing owing to a densely packed postsynaptic membrane. By disrupting membrane packing, these cells were switched to an NK-susceptible state, which could suggest strategies for improving cytotoxic cell-based cancer therapies. Thus, lipid membranes serve an unexpected role in NK cell functionality protecting them from autolysis, while degranulation allows for the inherent lytic granule membrane properties to create local ordered lipid "shields" against self-destruction.Yu LiJordan S OrangePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 8, p e3001328 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Yu Li Jordan S Orange Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.
description	Natural killer (NK) cells kill a target cell by secreting perforin into the lytic immunological synapse, a specialized interface formed between the NK cell and its target. Perforin creates pores in target cell membranes allowing delivery of proapoptotic enzymes. Despite the fact that secreted perforin is in close range to both the NK and target cell membranes, the NK cell typically survives while the target cell does not. How NK cells preferentially avoid death during the secretion of perforin via the degranulation of their perforin-containing organelles (lytic granules) is perplexing. Here, we demonstrate that NK cells are protected from perforin-mediated autolysis by densely packed and highly ordered presynaptic lipid membranes, which increase packing upon synapse formation. When treated with 7-ketocholesterol, lipid packing is reduced in NK cells making them susceptible to perforin-mediated lysis after degranulation. Using high-resolution imaging and lipidomics, we identified lytic granules themselves as having endogenously densely packed lipid membranes. During degranulation, lytic granule-cell membrane fusion thereby further augments presynaptic membrane packing, enhancing membrane protection at the specific sites where NK cells would face maximum concentrations of secreted perforin. Additionally, we found that an aggressive breast cancer cell line is perforin resistant and evades NK cell-mediated killing owing to a densely packed postsynaptic membrane. By disrupting membrane packing, these cells were switched to an NK-susceptible state, which could suggest strategies for improving cytotoxic cell-based cancer therapies. Thus, lipid membranes serve an unexpected role in NK cell functionality protecting them from autolysis, while degranulation allows for the inherent lytic granule membrane properties to create local ordered lipid "shields" against self-destruction.
format	article
author	Yu Li Jordan S Orange
author_facet	Yu Li Jordan S Orange
author_sort	Yu Li
title	Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.
title_short	Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.
title_full	Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.
title_fullStr	Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.
title_full_unstemmed	Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.
title_sort	degranulation enhances presynaptic membrane packing, which protects nk cells from perforin-mediated autolysis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/c15feb9cd1be4103b9d07e6b8758bbb8
work_keys_str_mv	AT yuli degranulationenhancespresynapticmembranepackingwhichprotectsnkcellsfromperforinmediatedautolysis AT jordansorange degranulationenhancespresynapticmembranepackingwhichprotectsnkcellsfromperforinmediatedautolysis
_version_	1718375924835024896

Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis.

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