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

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. NGLY1 mutations cause a multisystem developmental disorder. Here they show that this enzyme is required for normal gut barrier function, and when mutated, causes immune and metabolic abnormalities, contributing to lethality.

Automated summary

Intestinal barrier dysfunction can cause inflammation and metabolic changes. However, the impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. This study establishes that loss of Drosophila N-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. Loss of Pngl also results in immune and metabolic abnormalities, contributing to lethality.