Gut Barrier Defects, Intestinal Immune Hyperactivation and Enhanced Lipid Catabolism Drive Lethality in NGLY1-Deficient Drosophila

Authors

Ashutosh Pandey
Antonio Galeone
Seung Yeop Han
Benjamin A Story
Gaia Consonni
William F Mueller
Lars M Steinmetz
Thomas Vaccari
Hamed Jafar-Nejad

Publication Date

9-13-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-40910-w

PMID

37704604

PMCID

PMC10499810

PubMedCentral® Posted Date

9-13-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Drosophila, Lipolysis, Adipose Tissue, Enterocytes, Lipids, Developmental biology, Genetics, Innate immunity, Glycosylation

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.