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

Authors :
Logeay R
Paul F. Langton
Michael E. Baumgartner
Eugenia Piddini
Source :
PLoS Genetics, PLoS Genetics, Vol 17, Iss 12, p e1009946 (2021), Langton, P F, Baumgartner, M E, Logeay, R & Piddini, E 2021, ' Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status ', PLoS Genetics, vol. 17, no. 2, e1009946 . https://doi.org/10.1371/journal.pgen.1009946
Publication Year :
2021
Publisher :
Public Library of Science, 2021.

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.<br />Author summary Removal of damaged cells is important for maintaining tissue health and preventing disease. 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. Cells carrying a mutation in Minute genes are said to behave as losers, as over time, they are eliminated by competition with surrounding wild type cells. It is known that toxic protein aggregates in the cytoplasm contribute to the loser status of Minute cells. The factors Xrp1 and Irbp18 are also required for the elimination of Minute cells. Here we uncover the relationship between these factors and toxic protein aggregates in cell competition. We find that Xrp1 and Irbp18 promote protein aggregate formation and that, vice versa, protein aggregates induce Xrp1 and Irbp18 activity. This amplifies stress signalling and reduces the fitness of Minute cells, leading to their removal from tissues through cell competition. These findings shed light on an important mechanism by which cells carrying certain types of damage can be eliminated to preserve organism health.

Details

Language :
English
ISSN :
15537404 and 15537390
Volume :
17
Issue :
12
Database :
OpenAIRE
Journal :
PLoS Genetics
Accession number :
edsair.doi.dedup.....f75f23f1653f3ceae2faa11158283fff
Full Text :
https://doi.org/10.1371/journal.pgen.1009946