Damage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut

• Published in: Nature communications Vol. 10; no. 1; pp. 4365 - 14
• Main Authors: Patel, Parthive H., Pénalva, Clothilde, Kardorff, Michael, Roca, Marianne, Pavlović, Bojana, Thiel, Anja, Teleman, Aurelio A., Edgar, Bruce A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-09-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 14/19; 38/77; 38/90; 631/532/2063; 631/532/2118/2437; 631/532/2139; 631/532/489; 631/80/86/2366; 64/24; Animals; Animals, Genetically Modified; Bacterial Infections - microbiology; Cell activation; Damage; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Enterocytes; Enterocytes - metabolism; Enterocytes - microbiology; Exposure; Humanities and Social Sciences; Infections; Insects; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - physiopathology; Intestine; Intestines - microbiology; Intestines - pathology; Intestines - physiopathology; Kinases; MAP kinase; MAP Kinase Kinase 3 - genetics; MAP Kinase Kinase 3 - metabolism; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Midgut; multidisciplinary; NAD(P)H oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Organic chemistry; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Reactive oxygen species; Regeneration; Regeneration - genetics; Regeneration - physiology; Science; Science (multidisciplinary); Signal Transduction; Signaling; Stem cells; Stem Cells - metabolism; Stem Cells - microbiology; Stress, Mechanical; Wounding
• ISSN: 2041-1723; 2041-1723
• 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.
Epithelia are exposed to diverse types of environmental stress, but the mechanisms by which epithelial cells sense stress are not well understood. Here, the authors show that a Nox-ROS-Ask1-MKK3-p38 signaling axis integrates various types of stress to promote intestinal regeneration.