Rotavirus-mediated DGAT1 degradation: A pathophysiological mechanism of viral-induced malabsorptive diarrhea.
Zheng LiuHunter SmithJeanette M CriglarAntonio J ValentinUmesh KarandikarXi-Lei ZengMary K EstesSue E CrawfordPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and ~128,000 deaths annually in infants and children. RV-induced mechanisms that result in diarrhea are not completely understood, but malabsorption is a contributing factor. RV alters cellular lipid metabolism by inducing lipid droplet (LD) formation as a platform for replication factories named viroplasms. A link between LD formation and gastroenteritis has not been identified. We found that diacylglycerol O-acyltransferase 1 (DGAT1), the terminal step in triacylglycerol synthesis required for LD biogenesis, is degraded in RV-infected cells by a proteasome-mediated mechanism. RV-infected DGAT1-silenced cells show earlier and increased numbers of LD-associated viroplasms per cell that translate into a fourfold-to-fivefold increase in viral yield ( P < 0.05). Interestingly, DGAT1 deficiency in children is associated with diarrhea due to altered trafficking of key ion transporters to the apical brush border of enterocytes. Confocal microscopy and immunoblot analyses of RV-infected cells and DGAT1 -/- human intestinal enteroids (HIEs) show a decrease in expression of nutrient transporters, ion transporters, tight junctional proteins, and cytoskeletal proteins. Increased phospho-eIF2α (eukaryotic initiation factor 2 alpha) in DGAT1 -/- HIEs, and RV-infected cells, indicates a mechanism for malabsorptive diarrhea, namely inhibition of translation of cellular proteins critical for nutrient digestion and intestinal absorption. Our study elucidates a pathophysiological mechanism of RV-induced DGAT1 deficiency by protein degradation that mediates malabsorptive diarrhea, as well as a role for lipid metabolism, in the pathogenesis of gastroenteritis.
Keyphrases
- mycobacterium tuberculosis
- induced apoptosis
- cell cycle arrest
- irritable bowel syndrome
- high glucose
- clostridium difficile
- sars cov
- endothelial cells
- endoplasmic reticulum stress
- diabetic rats
- single cell
- type diabetes
- young adults
- high throughput
- cell death
- cardiovascular disease
- stem cells
- signaling pathway
- small molecule
- cell proliferation
- fatty acid
- risk factors
- bone marrow
- drug induced
- cell therapy
- protein protein