Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α.

Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells ('losers') are eliminated from the tissue when confronted with fitter cells ('winners'). Despite extensive studies, the mechanism that drives loser's death and its physiological triggers remained elusive. Here, through a genetic screen in Drosophila, we find that endoplasmic reticulum (ER) stress causes cell competition. Mechanistically, ER stress upregulates the bZIP transcription factor Xrp1, which promotes phosphorylation of the eukaryotic translation initiation factor eIF2α via the kinase PERK, leading to cell elimination. Surprisingly, our genetic data show that different cell competition triggers such as ribosomal protein mutations or RNA helicase Hel25E mutations converge on upregulation of Xrp1, which leads to phosphorylation of eIF2α and thus causes reduction in global protein synthesis and apoptosis when confronted with wild-type cells. These findings not only uncover a core pathway of cell competition but also open the way to understanding the physiological triggers of cell competition. Author summary: Cell competition is an evolutionarily conserved quality control process that selectively eliminates viable unfit cells ('losers') when coexisting with fitter cells ('winners') within a growing tissue. A common feature of loser mutants is a reduction in protein synthesis rate. Recent studies have shown that the bZIP transcription factor Xrp1 causes reduction in protein synthesis in ribosomal protein-mutant losers, while the mechanism by which Xrp1 reduces protein synthesis remained unknown. Here, through a genetic screen in Drosophila, we find that mutations causing ER stress make cells losers when surrounded by wild-type cells. Mechanistically, cells undergoing ER stress upregulate Xrp1, which promotes phosphorylation of the eukaryotic translation initiation factor eIF2α via the kinase PERK, thereby reducing global protein synthesis and inducing cell death. Crucially, this mechanism also drives cell competition triggered by ribosomal protein or Hel25E mutations, both of which cause reduction in protein synthesis rate. Our findings show that cell competition is commonly driven by Xrp1-mediated phosphorylation of eIF2α and that ER stress or other environmental stresses activating integrated stress response signaling, which converge on the phosphorylation of eIF2α, could be a physiological trigger of cell competition. [ABSTRACT FROM AUTHOR]