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Rotavirus-mediated DGAT1 degradation: A pathophysiological mechanism of viral-induced malabsorptive diarrhea.

Authors :
Zheng Liu
Smith, Hunter
Criglar, Jeanette M.
Valentin, Antonio J.
Karandikar, Umesh
Xi-Lei Zeng
Estes, Mary K.
Crawford, Sue E.
Source :
Proceedings of the National Academy of Sciences of the United States of America. 12/19/2023, Vol. 120 Issue 51, p1-9. 18p.
Publication Year :
2023

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
120
Issue :
51
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
174430714
Full Text :
https://doi.org/10.1073/pnas.2302161120