Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth

Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by...

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Published in:	PLoS genetics Vol. 20; no. 2; p. e1011171
Main Authors:	Paul, Pranab Kumar, Umarvaish, Shruti, Bajaj, Shivani, S, Rishana Farin, Mohan, Hrudya, Annaert, Wim, Chaudhary, Varun
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 26-02-2024 Public Library of Science (PLoS)
Subjects:	Animals Apoptosis Biology and Life Sciences Cell death Cell growth Cell survival Cell Survival - genetics Cellular proteins Cloning Competition Competitive advantage Drosophila Drosophila - genetics Drosophila - metabolism Endoplasmic reticulum Epithelium Genes Genetic aspects Golgi apparatus Golgi Apparatus - metabolism Homeostasis Insects Kinases Medicine and Health Sciences Membrane Glycoproteins - metabolism Metabolism Mutation Myc protein Phosphorylation Physical Sciences Physiological aspects Proteins Proteostasis - genetics Research and Analysis Methods Statistical analysis Transcription factors India
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Summary:	Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by the healthier neighbors. The precise connection between proteotoxic stress and competitive cell survival remains largely elusive. Here, we reveal the function of an endoplasmic reticulum (ER) and Golgi localized protein Rer1 in the regulation of protein homeostasis in the developing Drosophila wing epithelium. Our results show that loss of Rer1 leads to proteotoxic stress and PERK-mediated phosphorylation of eukaryotic initiation factor 2α. Clonal analysis showed that rer1 mutant cells are identified as losers and eliminated through cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc-overexpression that causes overgrowth, albeit under high proteotoxic stress. Our results suggest that increased levels of Rer1 provide cytoprotection to Myc-overexpressing cells by alleviating the proteotoxic stress and thereby supporting Myc-driven overgrowth. In summary, these observations demonstrate that Rer1 acts as a novel regulator of proteostasis in Drosophila and reveal its role in competitive cell survival.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1011171