Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction

A decline in protein homeostasis (proteostasis) has been proposed as a hallmark of aging. Somatic stem cells (SCs) uniquely maintain their proteostatic capacity through mechanisms that remain incompletely understood. Here, we describe and characterize a 'proteostatic checkpoint' in Drosoph...

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Published inNature communications Vol. 10; no. 1; p. 1050
Main Authors Rodriguez-Fernandez, Imilce A, Qi, Yanyan, Jasper, Heinrich
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 05.03.2019
Nature Publishing Group UK
Nature Portfolio
Subjects
Aging
Aging - physiology
Animals
Animals, Genetically Modified
Cell cycle
Cell Cycle Checkpoints - physiology
Drosophila
Drosophila melanogaster
Drosophila Proteins - metabolism
Epithelial Cells - physiology
Epithelium - physiology
Female
Homeostasis
Intestinal Mucosa - cytology
Intestinal Mucosa - physiology
Intestine
Life span
Longevity
Nuclear Proteins - metabolism
Overexpression
Proteins
Proteolysis
Proteostasis - physiology
Repressor Proteins - metabolism
Stem cells
Stem Cells - physiology
Transcription activation
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Summary:A decline in protein homeostasis (proteostasis) has been proposed as a hallmark of aging. Somatic stem cells (SCs) uniquely maintain their proteostatic capacity through mechanisms that remain incompletely understood. Here, we describe and characterize a 'proteostatic checkpoint' in Drosophila intestinal SCs (ISCs). Following a breakdown of proteostasis, ISCs coordinate cell cycle arrest with protein aggregate clearance by Atg8-mediated activation of the Nrf2-like transcription factor cap-n-collar C (CncC). CncC induces the cell cycle inhibitor Dacapo and proteolytic genes. The capacity to engage this checkpoint is lost in ISCs from aging flies, and we show that it can be restored by treating flies with an Nrf2 activator, or by over-expression of CncC or Atg8a. This limits age-related intestinal barrier dysfunction and can result in lifespan extension. Our findings identify a new mechanism by which somatic SCs preserve proteostasis, and highlight potential intervention strategies to maintain regenerative homeostasis.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-08982-9