Abstract
The Unfolded Protein Response of the endoplasmic reticulum (UPRER) controls proteostasis by adjusting the protein folding capacity of the ER to environmental and cell-intrinsic conditions. In metazoans, loss of proteostasis results in degenerative and proliferative diseases and cancers. The cellular and molecular mechanisms causing these phenotypes remain poorly understood. Here we show that the UPRER is a critical regulator of intestinal stem cell (ISC) quiescence in Drosophila melanogaster. We find that ISCs require activation of the UPRER for regenerative responses, but that a tissue-wide increase in ER stress triggers ISC hyperproliferation and epithelial dysplasia in aging animals. These effects are mediated by ISC-specific redox signaling through Jun-N-terminal Kinase (JNK) and the transcription factor CncC. Our results identify a signaling network of proteostatic and oxidative stress responses that regulates ISC function and regenerative homeostasis in the intestinal epithelium.
Highlights
Long-term homeostasis of high-turnover tissues relies on the precise regulation of stem cell (SC) activity that allows tailoring regenerative responses to the needs of the tissue
We identify a coordinated role of unfolded protein response of the endoplasmic reticulum (ER) (UPRER) and oxidative stress signaling in regulating the proliferation of intestinal stem cells (ISCs)
This function is dependent on the activities of the stress sensor Jun-N-terminal Kinase (JNK) and the redox-responsive transcription factor CncC, which we have previously identified as regulators of ISC proliferation
Summary
Long-term homeostasis of high-turnover tissues relies on the precise regulation of stem cell (SC) activity that allows tailoring regenerative responses to the needs of the tissue. The UPRER is triggered by the accumulation of misfolded proteins in the ER [8], which activate three highly conserved UPRER sensors: the PKR-like ER kinase PERK, the transcription factor ATF6, and the endoribonuclease IRE1 (Figure 1B) These sensors make up the three branches of UPRER signaling, which consists of IRE1-mediated splicing of the mRNA encoding the bZip transcription factor X-Box binding protein 1 (Xbp1), phosphorylation of the translation initiation factor 2 alpha (eIF2a) by PERK, and cleavage and activation of ATF6, resulting in its nuclear translocation and activation of stress response genes, including Xbp1 [1,2,3,4,5,6,7,9]. The accumulation of un/misfolded proteins in the ER is further associated with increased production of reactive oxygen species (ROS), most likely due to the production of hydrogen peroxide as a byproduct of protein disulfide bond formation by protein disulfide isomerase (PDI) and ER oxidoreductin 1 (Ero1) [13,14,15]
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