Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status.

Paul F Langton,Remi Logeay,Eugenia Piddini,Michael E Baumgartner,Norbert Perrimon

doi:10.1371/journal.pgen.1009946

Abstract

Cell competition induces the elimination of less-fit "loser" cells by fitter "winner" cells. In Drosophila, cells heterozygous mutant in ribosome genes, Rp/+, known as Minutes, are outcompeted by wild-type cells. Rp/+ cells display proteotoxic stress and the oxidative stress response, which drive the loser status. Minute cell competition also requires the transcription factors Irbp18 and Xrp1, but how these contribute to the loser status is partially understood. Here we provide evidence that initial proteotoxic stress in RpS3/+ cells is Xrp1-independent. However, Xrp1 is sufficient to induce proteotoxic stress in otherwise wild-type cells and is necessary for the high levels of proteotoxic stress found in RpS3/+ cells. Surprisingly, Xrp1 is also induced downstream of proteotoxic stress, and is required for the competitive elimination of cells suffering from proteotoxic stress or overexpressing Nrf2. Our data suggests that a feed-forward loop between Xrp1, proteotoxic stress, and Nrf2 drives Minute cells to become losers.

Highlights

Cells within a tissue may become damaged due to spontaneous or environmentally induced mutations, and it is beneficial to organismal health if these cells are removed and replaced by healthy cells
Cells that become damaged by mutation or due to aging are actively eliminated from tissues by their fitter neighbouring cells through a process called cell competition
Cell competition was discovered in Drosophila through the study of Minute mutants, which are a class of mutations in ribosomal genes

Summary

Introduction

Cells within a tissue may become damaged due to spontaneous or environmentally induced mutations, and it is beneficial to organismal health if these cells are removed and replaced by healthy cells. Cell competition promotes tissue health and is thought to provide a level of protection against developmental aberrations [4,5,6] and against cancer by removing cells carrying oncoplastic mutations [1,7]. An increasing body of evidence indicates that cell competition can promote growth of established tumours, enabling them to expand at the expense of surrounding healthy cells [7,8]. Minute cell competition was discovered through the study of a class of Drosophila ribosomal mutations called Minutes [9] and initial work suggests that it is conserved in mammals [10]. Rp/+ tissues display a higher cell-autonomous death frequency than wild-type tissues [12,13,14,15], and competitive interactions further elevate cell death in Rp/+ cells bordering wild-type cells, contributing to progressive loss of Rp/+ cells over time [14,16,17]

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Discussion

Conclusion