RIPK3 Activation Leads to Cytokine Synthesis that Continues after Loss of Cell Membrane Integrity
This week we profile a recent publication in Cell Reports from the laboratory of Dr. Andrew Oberst (pictured) at UW.
What is the significance of the findings in this publication?
In the past, we’ve found that activation of “necroptosis,” which is a form of programmed cell death caused by viral infection, is accompanied by the production of a bunch of cytokines and chemokines. What’s been a mystery is how a dying cell can pull this off, i.e. how it is able to produce a bunch of these signaling molecules while it’s dying. What our new paper finds is that necroptotic cells are actually able to continue translating protein even after their cell membranes have burst. They do this by keeping the endoplasmic reticulum intact; these necroptotic cell “corpses” are thereby able to keep translating messenger RNA for several hours after they are apparently “dead”. This is interesting from a pure biology standpoint, as we typically think of loss of cell membrane integrity as the “end” of a cell. We also show that this ongoing cytokine synthesis from “zombie” cells allows macrophages to find these cells and eat them more readily in vivo, and also contributes by alerting T cells to antigens present in these dying cells. An interesting possibility is that when a virally infected cell undergoes necroptosis, it bursts its membrane to deny the virus a replicative niche, but also continues to produce cytokines to activate the immune system.