RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity

Orozco, S. L. et al. (2019) RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity. Cell Reports, 28(9), 2275-2287.e5. (doi: 10.1016/j.celrep.2019.07.077) (PMID:31461645) (PMCID:PMC6857709)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by NIH grants R01AI132595 and R01CA228098 and a CRI Wade F. B. Thompson CLIP award (to A.O.) and an NIH NIAID R01 Diversity Supplement (to S.L.O.).
• Keywords: MLKL, RIPK3, cell death, cytokines, necroptosis, phagocytosis.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tait, Professor Stephen
• Authors: Orozco, S. L., Daniels, B. P., Yatim, N., Messmer, M. N., Quarato, G., Chen-Harris, H., Cullen, S. P., Snyder, A. G., Ralli-Jain, P., Frase, S., Tait, S. W.G., Green, D. R., Albert, M. L., and Oberst, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 27 August 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Cell Reports 28(9):2275-2287.e5
• Publisher Policy: Reproduced under a Creative Commons License