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Dual roles of USP39 in stabilizing PB2 and orchestrating ribonucleoprotein assembly drive H5 influenza virus

Hui Yang1, Yurui Dong2, Ying Bian2

  • 1College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou, Jiangsu 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Research Centre of Engineering and Technology for Prevention and Control of Poultry Disease, Yangzhou, Jiangsu 225009, China; Jiangsu Interdisciplinary Center for Zoonoses and Biosafety, Yangzhou University, Yangzhou 225009, China.

Cell Reports
|February 19, 2026
PubMed

Insights

Avian influenza virus (AIV) evades host defenses by hijacking USP39, a protein that prevents viral polymerase degradation and aids replication. This discovery offers a new target for developing antivirals against H5 AIV.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Host cells target avian influenza virus (AIV) polymerase PB2 for degradation as an antiviral defense.
  • The viral mechanisms to counteract PB2 degradation and sustain replication were previously unclear.

Purpose of the Study:

  • To identify host proteins interacting with H5 AIV PB2.
  • To elucidate the role of USP39 in AIV replication and host immune evasion.

Main Methods:

  • Co-immunoprecipitation to identify host proteins interacting with H5 AIV PB2.
  • Biochemical assays to assess USP39's deubiquitinase activity and its effect on PB2.
  • In vitro viral replication assays and in vivo pathogenicity studies in mice.

Main Results:

  • USP39 was identified as a deubiquitinase that directly deubiquitinates H5 AIV PB2 at K660, preventing its degradation.
  • USP39 also promotes PB2-PB1 association, independent of its enzymatic activity, facilitating ribonucleoprotein (RNP) complex formation.
  • A PB2 K660R substitution mutant enhanced viral replication and mouse pathogenicity.

Conclusions:

  • AIV hijacks USP39 to counteract host ubiquitination, sustain polymerase activity, and facilitate RNP biogenesis.
  • USP39 plays a dual role in amplifying viral RNA synthesis and dampening host antiviral responses.
  • USP39 represents a potential therapeutic target for developing broad-spectrum antivirals against pandemic-prone H5 viruses.
Keywords:
CP: cell biologyCP: microbiologyPB2USP39avian influenza viruspathogenicityubiquitination

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