Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila

• Published in: Nature communications Vol. 14; no. 1; pp. 5667 - 16
• Main Authors: Pandey, Ashutosh, Galeone, Antonio, Han, Seung Yeop, Story, Benjamin A, Consonni, Gaia, Mueller, William F, Steinmetz, Lars M, Vaccari, Thomas, Jafar-Nejad, Hamed
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 13.09.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Abnormalities; Animal health; Bacteria; Catabolism; Defects; Digestive system; Digestive tract; Drosophila; Enterocytes; Fat body; Forkhead protein; Fruit flies; Germfree; Immune response; Immune system; Innate immunity; Insects; Intestine; Larvae; Lethality; Lipid metabolism; Lipids; Metabolism; Mutants; N-glycanase
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40910-w

Abstract Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N -glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of Pngl in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of Pngl mutants rescued their developmental delay but not lethality. However, raising Pngl mutants on isocaloric, fat-rich diets partially rescued lethality. Our data indicate that Pngl functions in Drosophila larvae to establish the gut barrier, and that the lethality caused by loss of Pngl is primarily mediated through non-bacterial induction of immune and metabolic abnormalities.