Elizabeth Blackwell Institute for Health Research, University of Bristol, Bristol, BS8 1UH, UK.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
Nat Commun. 2019 Sep 25;10(1):4365. doi: 10.1038/s41467-019-12336-w.
Epithelia are exposed to diverse types of stress and damage from pathogens and the environment, and respond by regenerating. Yet, the proximal mechanisms that sense epithelial damage remain poorly understood. Here we report that p38 signaling is activated in adult Drosophila midgut enterocytes in response to diverse stresses including pathogenic bacterial infection and chemical and mechanical insult. Two upstream kinases, Ask1 and Licorne (MKK3), are required for p38 activation following infection, oxidative stress, detergent exposure and wounding. Ask1-p38 signaling in enterocytes is required upon infection to promote full intestinal stem cell (ISC) activation and regeneration, partly through Upd3/Jak-Stat signaling. Furthermore, reactive oxygen species (ROS) produced by the NADPH oxidase Nox in enterocytes, are required for p38 activation in enterocytes following infection or wounding, and for ISC activation upon infection or detergent exposure. We propose that Nox-ROS-Ask1-MKK3-p38 signaling in enterocytes integrates multiple different stresses to induce regeneration.
上皮细胞暴露于病原体和环境中的多种类型的应激和损伤下，并通过再生来响应。然而，感知上皮损伤的近端机制仍知之甚少。在这里，我们报告在成年果蝇中肠肠细胞中，p38 信号在多种应激包括病原体细菌感染、化学和机械损伤后被激活。在感染、氧化应激、去污剂暴露和创伤后，两种上游激酶 Ask1 和 Licorne（MKK3）被要求激活 p38。感染后肠细胞中的 Ask1-p38 信号对于促进完全的肠道干细胞（ISC）激活和再生是必需的，部分是通过 Upd3/Jak-Stat 信号。此外，在感染或创伤后，肠细胞中的 NADPH 氧化酶 Nox 产生的活性氧（ROS）对于感染或去污剂暴露后肠细胞中 p38 的激活以及感染或去污剂暴露后 ISC 的激活是必需的。我们提出，肠细胞中的 Nox-ROS-Ask1-MKK3-p38 信号整合了多种不同的应激以诱导再生。
