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Orozco, Susana L.; Daniels, Brian P.; Yatim, Nader; Messmer, Michelle N.; Quarato, Giovanni; Chen-Harris, Haiyin; Cullen, Sean P.; Snyder, Annelise G.; Ralli-Jain, Pooja; Frase, Sharon; Tait, Stephen W.G.; Green, Douglas R.; Albert, Matthew L.; Oberst, Andrew
Cell reports, 08/2019, Letnik: 28, Številka: 9Journal Article
Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3 and subsequent cell membrane permeabilization by the effector MLKL. RIPK3 activation can also promote immune responses via production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells even after they have lost cell membrane integrity and irreversibly committed to death. This continued cytokine production is dependent on mRNA translation and requires maintenance of endoplasmic reticulum integrity that remains after plasma membrane integrity is lost. The continued translation of cytokines by cellular corpses contributes to necroptotic cell uptake by innate immune cells and priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells. Display omitted •RIPK3 activation induces both necroptotic cell death and cytokine production•Cytokine mRNA continues to be translated even after plasma membrane rupture•mRNA translation requires ER function, which remains after plasma membrane rupture•Continued cytokine synthesis contributes to the immune response to necroptotic cells Necroptotic cell death is associated with cytokine production. Orozco et al. show that necroptotic cell “corpses” continue to synthesize cytokines after they have lost membrane integrity and committed to cell death. This activity involves continued mRNA translation and requires ER function that continues after plasma membrane rupture.
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