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Abstract
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.
Highlights
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 [1,2,3]
Recent studies have shown that the basic leucine zipper domain (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
Through a genetic screen in Drosophila, we find that mutations causing endoplasmic reticulum (ER) stress make cells losers when surrounded by wild-type cells
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 [1,2,3]. Drosophila cells homozygously mutant for Mahjong/VprBP (Mahj) [5] or the RNA helicase Helicase25E (Hel25E) [6] are viable on their own but are eliminated by apoptosis when confronted with wild-type cells. Xrp upregulation is required for M/+ cells to reduce protein synthesis levels [15]. The mechanisms of how Xrp reduces protein synthesis and how it contributes to loser’s death remained unknown. We have recently found that, to M/+ clones, loser clones such as Hel25E or Mahj mutant clones reduce protein synthesis levels compared to neighboring wild-type winners [6], which suggests a potential mechanistic link between the reduction of protein synthesis and induction of loser’s death
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