LAUSR

Cellular stress granules arise in cells subjected to stress and promote cell survival. A cellular protein that localizes to stress granules is Z-DNA–binding protein 1 (ZBP1), which plays a major role in necroptosis, a programmed cell death pathway mediated by the kinase RIPK3. Here, we showed that the stress granule inducer arsenite activated RIPK3-dependent necroptosis. This pathway required ZBP1, which localized to arsenite-induced stress granules. RIPK3 localized to stress granules in the presence of ZBP1, leading to the formation of ZBP1-RIPK3 necrosomes, phosphorylation of the RIPK3 effector MLKL, and execution of necroptosis. Cells that did not form stress granules did not induce necroptosis in response to arsenite. Together, these results show that arsenite induces ZBP1-mediated necroptosis in a manner dependent on stress granule formation. Description ZBP1 induces stress granule–dependent necroptosis in cells subjected to oxidative stress. Stressed into dying by necroptosis Cell stress induces the formation of stress granules, nonmembranous structures consisting of stalled translation complexes, which can be released to enable RNA translation to resume after the stress has subsided. Szczerba et al. uncovered a role for stress granules in oxidative stress–induced necroptosis, a regulated cell death pathway resulting from plasma membrane punctures generated by the protein MLKL after its phosphorylation by the kinase RIPK3. The Z-DNA–binding protein ZBP1 recruited RIPK3 to stress granules to induce necroptosis in response to arsenite, an environmental contaminant that causes oxidative stress. These results reveal a role for stress granules and ZBP1 in the regulation of necroptosis in cells subjected to oxidative stress. —WW