title: PERK Limits Drosophila Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress.
abstract: Intestinal homeostasis requires precise control of intestinal stem cell (ISC) proliferation. In Drosophila, this control declines with age largely due to chronic activation of stress signaling and associated chronic inflammatory conditions. An important contributor to this condition is the age-associated increase in endoplasmic reticulum (ER) stress. Here we show that the PKR-like ER kinase (PERK) integrates both cell-autonomous and non-autonomous ER stress stimuli to induce ISC proliferation. In addition to responding to cell-intrinsic ER stress, PERK is also specifically activated in ISCs by JAK/Stat signaling in response to ER stress in neighboring cells. The activation of PERK is required for homeostatic regeneration, as well as for acute regenerative responses, yet the chronic engagement of this response becomes deleterious in aging flies. Accordingly, knocking down PERK in ISCs is sufficient to promote intestinal homeostasis and extend lifespan. Our studies highlight the significance of the PERK branch of the unfolded protein response of the ER (UPRER) in intestinal homeostasis and provide a viable strategy to improve organismal health- and lifespan.
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: 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: Yanyan
authors.initials: Y
authors.lastname: Qi
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; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006706:Homeostasis; D007422:Intestines / Q000166:cytology*; D018384:Oxidative Stress; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D050862:Oxidoreductases Acting on Sulfur Group Donors; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; C532250:Ero1l protein, Drosophila