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ZDHHC18-Mediated Palmitoylation of ORF3a Promotes SARS-CoV-2 Pathogenesis by Antagonizing TRIM16-Mediated

Sidi Yang1,2, Kun Li3, Lihong Liu1,2

  • 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 10, 2026
PubMed

Insights

Palmitoylation stabilizes SARS-CoV-2 ORF3a protein by preventing its degradation. Inhibiting this process with a peptide reduced viral pathogenicity, offering a potential therapeutic strategy against SARS-CoV-2.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • SARS-CoV-2 accessory protein ORF3a drives viral pathogenesis via membrane remodeling, immune evasion, and inflammation.
  • The precise molecular mechanisms of ORF3a pathogenesis are not fully understood, and targeted therapies are lacking.

Purpose of the Study:

  • To elucidate the role of post-translational modifications in regulating ORF3a function and pathogenesis.
  • To identify potential therapeutic targets within the ORF3a regulatory pathway.

Main Methods:

  • Investigated palmitoylation of ORF3a using biochemical assays.
  • Identified ZDHHC18 as the palmitoyltransferase responsible for ORF3a modification at Cys130/Cys133.
  • Assessed the impact of palmitoylation on ORF3a stability, ubiquitination, and viral replication.
  • Developed and tested an ORF3a-mimicking palmitoylation-inhibitory peptide (OPIP).

Main Results:

  • Demonstrated that ZDHHC18-mediated palmitoylation stabilizes ORF3a by inhibiting proteasomal degradation.
  • Showed that palmitoylation prevents TRIM16-dependent K27-linked polyubiquitination of ORF3a.
  • Found that OPIP treatment blocked ORF3a palmitoylation, enhanced its degradation, and reduced SARS-CoV-2 pathogenicity.
  • ORF3a palmitoylation was linked to enhanced viral replication and inflammatory responses.

Conclusions:

  • ZDHHC18-mediated palmitoylation is a key regulator of ORF3a stability and SARS-CoV-2 virulence.
  • Targeting ORF3a palmitoylation represents a promising therapeutic strategy to combat SARS-CoV-2 infection.
Keywords:
ORF3aSARS‐CoV‐2palmitoylationviral pathogenesis

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