title: Integration of UPRER and oxidative stress signaling in the control of intestinal stem cell proliferation.
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.
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Lifen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Xiankun
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Hyung Don
authors.initials: HD
authors.lastname: Ryoo
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Jasper
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; D012097:Repressor Proteins; C116463:cnc protein, Drosophila; D048670:MAP Kinase Kinase 4