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

Pak-Hin Hinson Cheung; Tak-Wang Terence Lee; Chun Kew; Honglin Chen; Kwok-Yung Yuen; Chi-Ping Chan; Dong-Yan Jin

doi:10.1371/journal.ppat.1008611

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.

Authors

Pak-Hin Hinson Cheung¹, Tak-Wang Terence Lee¹, Chun Kew¹, Honglin Chen², Kwok-Yung Yuen², Chi-Ping Chan¹, Dong-Yan Jin¹

Affiliations

¹ School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
² State Key Laboratory for Emerging Infectious Diseases and Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.

Abstract

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*

Substances

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

Grants and funding

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.