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Pestiviruses utilize pyrimidine metabolism to regulate mitophagy for viral replication

Bingqian Zhao1,2,3, Jing Chen1, Yan Cheng1,2

  • 1MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.

Autophagy
|April 13, 2026
PubMed

Insights

Dihydroorotate dehydrogenase (DHODH) regulates autophagy and mitophagy, impacting Flaviviridae viral replication. DHODH deficiency impairs replication for some viruses while enhancing it for others, revealing its complex role in antiviral defense.

Area of Science:

  • Virology
  • Cell Biology
  • Metabolism

Background:

  • Dihydroorotate dehydrogenase (DHODH) is crucial for programmed cell death but its role in autophagy is unclear.
  • Flaviviridae viruses, significant public health threats, rely on autophagy for replication.
  • Previous work identified DHODH as a broad-spectrum target for Flaviviridae and a key regulator of Pestiviruses replication.

Purpose of the Study:

  • To investigate the role of DHODH in Flaviviridae replication through autophagy regulation.
  • To elucidate the genus-specific mechanisms of DHODH in controlling viral replication.
  • To identify DHODH as a potential antiviral target.

Main Methods:

  • RNA-sequencing screening and functional validation.
  • Analysis of autophagosome-lysosome fusion and autophagy flux.
  • Compound supplementation assays with pyrimidine precursors.
  • Investigation of classical swine fever virus NS4A interaction with DHODH and LC3.

Main Results:

  • DHODH regulates mitophagy, affecting Flaviviridae replication with genus-specific outcomes.
  • DHODH deficiency impairs autophagosome-lysosome fusion in autophagy-dependent Pestiviruses, suppressing replication.
  • In autophagy-inhibiting Flaviviruses, DHODH blockade enhances viral replication.
  • DHODH regulates autophagy via pyrimidine nucleotide metabolism.
  • CSFV NS4A recruits DHODH to mitochondria, activating mitophagy via interaction with LC3.

Conclusions:

  • DHODH plays a critical, virus genus-specific role in regulating Flaviviridae replication via the metabolism-autophagy axis.
  • DHODH is a promising antiviral target, with its regulation of mitophagy offering novel therapeutic strategies.
  • Understanding DHODH's interaction with viral proteins like CSFV NS4A is key for developing new antiviral drugs.
Keywords:
Autolysosome formationCSFVDHODHLIRmitophagyviral non-structural proteins

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