PERK Limits Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress

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The long-term maintenance of tissue homeostasis in barrier epithelia requires precise coordination of cellular stress and inflammatory responses with regenerative processes. This coordination is lost with age, resulting in degenerative and proliferative diseases. The Unfolded Protein Response of the Endoplasmic Reticulum (UPRER) is emerging as a central regulator of tissue homeostasis in barrier epithelia. The UPRER adjusts the protein folding capacity of the ER in response to protein stress in stem cells and differentiated cells, and thus influences proliferative homeostasis, cell differentiation and epithelial inflammatory responses. How these responses are coordinated to maintain epithelial homeostasis in aging organisms remains unclear. In a previous study, we have found that the UPRER controls intestinal stem cell (ISC) proliferation in the Drosophila intestinal epithelium by influencing the intracellular redox state. How signaling through the canonical ER stress sensor PERK (PKR-like ER kinase) is integrated into this signaling network remained unclear. Here we show that PERK serves as a central regulator of ISC proliferation and tissue homeostasis in response ER stress. Strikingly, we find that within the intestinal epithelium, PERK is activated specifically in ISCs in response to both systemic and local ER stress, and is required for ISC proliferation under both homeostatic and stress conditions. We identify JAK/Stat signaling as an activator of PERK in ISCs in response to ER stress in neighboring cells, and find that the wide-spread age-associated increase in PERK activity in ISCs is a cause of age-related dysplasia in this tissue. Accordingly, limiting PERK activity in ISCs promotes homeostasis of the intestinal epithelium in old flies and extends lifespan.

Vyšlo v časopise: PERK Limits Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005220
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005220

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