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Host OTUB2 and viral PLpro stabilize NSP8 to promote SARS-CoV-2 replication

Wenying Gao1, Hongfei Wang2, Jingguo Xin1

  • 1Institute of Virology and AIDS Research, Centre of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130000, China.

Virologica Sinica
|July 27, 2026
PubMed

Insights

The host deubiquitinase OTUB2 stabilizes SARS-CoV-2 replication by protecting viral factors NSP8 and PLpro. Inhibiting OTUB2 reduces viral load and disease severity, offering a potential antiviral strategy.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • The ubiquitin-proteasome system (UPS) is crucial for antiviral immunity but is exploited by viruses.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication relies on host-viral protein interactions.

Purpose of the Study:

  • To investigate the role of host deubiquitinase OTUB2 in SARS-CoV-2 replication.
  • To elucidate the mechanism by which OTUB2 influences viral replication machinery.

Main Methods:

  • Biochemical assays to assess deubiquitination activity.
  • Cell culture models of SARS-CoV-2 infection.
  • In vivo studies using a hamster infection model.

Main Results:

  • OTUB2 stabilizes SARS-CoV-2 replication factor NSP8 via direct deubiquitination and stabilization of viral protease PLpro.
  • OTUB2-mediated stabilization enhances viral replication-transcription complex function.
  • OTUB2 promotes viral immune evasion by suppressing type I interferon signaling.
  • OTUB2 inhibition reduces viral replication and disease severity in vitro and in vivo.

Conclusions:

  • SARS-CoV-2 utilizes host OTUB2 to stabilize its replication machinery.
  • OTUB2 is a potential host-directed target for antiviral therapies against SARS-CoV-2.
Keywords:
DeubiquitinationNSP8OTUB2PLproSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

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