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

Zheng Liu1,2, Hunter Smith1, Jeanette M Criglar1

  • 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.

Proceedings of the National Academy of Sciences of the United States of America
|December 11, 2023
PubMed

Insights

Rotavirus gastroenteritis leads to malabsorption. Researchers found rotavirus degrades DGAT1, an enzyme crucial for lipid metabolism, causing diarrhea in children and increasing viral yield in cells.

Area of Science:

  • Virology
  • Gastroenterology
  • Cell Biology

Background:

  • Gastroenteritis, particularly rotavirus (RV) infection, is a major global health concern in young children.
  • RV infection alters cellular lipid metabolism, inducing lipid droplet (LD) formation, but its direct link to gastroenteritis pathogenesis is unclear.
  • Diacylglycerol O-acyltransferase 1 (DGAT1) is essential for LD biogenesis.

Purpose of the Study:

  • To investigate the role of DGAT1 in rotavirus pathogenesis and its link to malabsorptive diarrhea.
  • To elucidate the mechanism by which RV infection affects DGAT1 and its consequences on cellular function.

Main Methods:

  • Utilized RV-infected cells and DGAT1-silenced cells.
  • Employed proteasome degradation assays, confocal microscopy, and immunoblot analyses.
  • Analyzed DGAT1-/- human intestinal enteroids (HIEs) and RV-infected cells for protein expression and phosphorylation.

Main Results:

  • Rotavirus infection degrades DGAT1 via proteasome-mediated mechanisms.
  • DGAT1 deficiency in RV-infected cells leads to increased LD-associated viroplasms and a fourfold-to-fivefold increase in viral yield.
  • DGAT1 deficiency in children is linked to diarrhea due to altered ion transporter trafficking.
  • RV-infected cells and DGAT1-/- HIEs exhibit reduced expression of nutrient transporters, ion transporters, tight junctional proteins, and cytoskeletal proteins.
  • Increased phospho-eIF2α in DGAT1-/- HIEs and RV-infected cells suggests inhibited protein translation, contributing to malabsorptive diarrhea.

Conclusions:

  • RV infection induces malabsorptive diarrhea by degrading DGAT1, impairing lipid metabolism and cellular transport functions.
  • DGAT1 plays a critical role in intestinal homeostasis and nutrient absorption, and its dysfunction contributes to gastroenteritis pathogenesis.
  • Targeting DGAT1 or related lipid metabolism pathways may offer therapeutic strategies for rotavirus gastroenteritis.
Keywords:
DGAT1lipid dropletproteasome degradationrotavirusviroplasm

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