Loss of Rer1 causes proteotoxic stress that drives cell competition and inhibits Myc-driven overgrowth

Abstract

Cell competition is a developmental phenomenon that allows the selection of healthier cells in a developing tissue. In this process, cells with reduced fitness, conceivably due to harmful mutations, acquire the loser status and are eliminated by the fitter (winner) neighboring cells via juxtacrine cell-cell interactions. How various mutations trigger cell competition is an extensively studied question. However, the mechanism of cell competition remains largely elusive. In this study, we reveal previously unknown functions of an ER and Golgi localized protein Rer1 in the regulation of cell competition in the developing Drosophila wing epithelium. Our data show that loss of Rer1 leads to the proteotoxic stress marked by the increased phosphorylation of eIF2. The increased proteotoxic stress in the rer1 mutant cells led to their elimination via cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc overexpression, which generates super-competitive cells that overgrow at the expense of the normal neighboring cells. Loss of Rer1 also restricts the growth of Myc-induced super-competitive cells. Moreover, consistent with its known function as a negative regulator of the Notch pathway, our results show that the increased levels of Rer1 in Myc-overexpression led to the downregulation of Notch activity. In summary, these observations provide the first characterization of Rer1 in Drosophila and reveal its role in triggering cell competition via the regulation of proteotoxic stress.