Virus subtype-specific suppression of MAVS aggregation and activation by PB1-F2 protein of influenza A (H7N9) virus

PLoS Pathog. 2020 Jun 8;16(6):e1008611. doi: 10.1371/journal.ppat.1008611. eCollection 2020 Jun.


Human infection with avian influenza A (H5N1) and (H7N9) viruses causes severe respiratory diseases. PB1-F2 protein is a critical virulence factor that suppresses early type I interferon response, but the mechanism of its action in relation to high pathogenicity is not well understood. Here we show that PB1-F2 protein of H7N9 virus is a particularly potent suppressor of antiviral signaling through formation of protein aggregates on mitochondria and inhibition of TRIM31-MAVS interaction, leading to prevention of K63-polyubiquitination and aggregation of MAVS. Unaggregated MAVS accumulated on fragmented mitochondria is prone to degradation by both proteasomal and lysosomal pathways. These properties are proprietary to PB1-F2 of H7N9 virus but not shared by its counterpart in WSN virus. A recombinant virus deficient of PB1-F2 of H7N9 induces more interferon β in infected cells. Our findings reveal a subtype-specific mechanism for destabilization of MAVS and suppression of interferon response by PB1-F2 of H7N9 virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Dogs
  • HEK293 Cells
  • Humans
  • Influenza A Virus, H7N9 Subtype / genetics
  • Influenza A Virus, H7N9 Subtype / metabolism*
  • Influenza, Human / genetics
  • Influenza, Human / metabolism*
  • Influenza, Human / pathology
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Madin Darby Canine Kidney Cells
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism*
  • Signal Transduction*
  • THP-1 Cells
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • MAVS protein, human
  • PB1-F2 protein, Influenza A virus
  • Tripartite Motif Proteins
  • Viral Proteins
  • Interferon-beta
  • TRIM31 protein, human
  • Ubiquitin-Protein Ligases

Grant support

This work was supported by Hong Kong Health and Medical Research Fund (15140662, HKM-15-M01, 19180812 and 19181002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.