Wang Lifen, Ryoo Hyung Don, Qi Yanyan, Jasper Heinrich
Buck Institute for Research on Aging, Novato, California, United States of America.
Department of Cell Biology, New York University School of Medicine, New York, New York, United States of America.
PLoS Genet. 2015 May 6;11(5):e1005220. doi: 10.1371/journal.pgen.1005220. eCollection 2015 May.
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.
肠道稳态需要对肠道干细胞（ISC）增殖进行精确控制。在果蝇中，这种控制随着年龄增长而下降，这主要是由于应激信号的慢性激活以及相关的慢性炎症状态。内质网（ER）应激随年龄增长而增加是导致这种情况的一个重要因素。在此我们表明，蛋白激酶R样内质网激酶（PERK）整合细胞自主和非自主的内质网应激刺激以诱导ISC增殖。除了对细胞内源性内质网应激作出反应外，PERK还会在ISC中被JAK/Stat信号通路特异性激活，以响应邻近细胞中的内质网应激。PERK的激活对于稳态再生以及急性再生反应都是必需的，然而这种反应的长期持续在衰老果蝇中变得有害。因此，在ISC中敲低PERK足以促进肠道稳态并延长寿命。我们的研究突出了内质网未折叠蛋白反应（UPRER）中PERK分支在肠道稳态中的重要性，并提供了一种改善机体健康和寿命的可行策略。
