PB1-F2 amyloid-like fibers correlate with proinflammatory signaling and respiratory distress in influenza-infected mice

Chevalier, Christophe; Leymarie, Olivier; Sedano, Laura; Costa, Bruno Da; Richard, Charles-Adrien; Maisonnasse, Pauline; Réfrégiers, Matthieu; Jamme, Frédéric; Goffic, Ronan Le

doi:10.1016/j.jbc.2021.100885

Cited by 6 publications

(6 citation statements)

References 57 publications

(98 reference statements)

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“…Using Gene Ontology (GO), we analyzed the functions associated with these 10 proteins. A single GO-term was associated with this set of genes: “Basolateral plasma membrane” (FDR: 8.2 × 10 −6 ), confirming the affinity of PB1-F2 for membranes [ 27 , 28 , 36 ].…”

Section: Resultsmentioning

confidence: 55%

“…As a matter of fact, PB1-F2 can fibrillate within hydrophobic structures and therefore generate a cytopathic effect [ 28 ]. In addition, there is a correlation between fiber formation and the pro-inflammatory properties of PB1-F2 [ 27 ]. We therefore hypothesized that the two different effects on the inflammatory response of the PB1-F2 studied might be related to their ability to form fibers.…”

Section: Resultsmentioning

confidence: 99%

“…PB1-F2 protein of avian influenza A/Turkey/Italy/977/1999 [H7N1], human influenza A/Scotland/20/1974 [H3N2] and human influenza A/WSN/1933 [H1N1] viruses were expressed and purified as described previously [ 27 , 28 ]. Briefly, the gene encoding either full-length PB1-F2(1–90) protein were cloned into the pET22b+ expression vector (Novagen, Fontenay sous Bois, France) to express His6-tagged protein versions.…”

Section: Methodsmentioning

confidence: 99%

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Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus

Mettier

Prompt

Bruder

et al. 2023

Viruses

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Most influenza viruses express the PB1-F2 protein which is regarded as a virulence factor. However, PB1-F2 behaves differently in avian and mammalian hosts, suggesting that this protein may be involved in the species barrier crossings regularly observed in influenza viruses. To better understand the functions associated with this viral protein, we decided to compare the BioID2-derived proximity interactome of a human PB1-F2 from an H3N2 virus with that of an avian PB1-F2 from an H7N1 strain. The results obtained reveal that the two proteins share only a few interactors and thus common functions. The human virus protein is mainly involved in signaling by Rho GTPases while the avian virus protein is mainly involved in ribonucleoprotein complex biogenesis. PB1-F2 H3N2 interactors include several members of the 14-3-3 protein family, a family of regulatory proteins involved in many signaling pathways. We then validated the interaction with 14-3-3 proteins and were able to show that the association of H3N2-PB1-F2 with YWHAH increased the activity of the antiviral sensor MDA5, while H7N1-PB1-F2 had no effect. Collectively, these results show that PB1-F2 can associate with a large range of protein complexes and exert a wide variety of functions. Furthermore, PB1-F2 interactome differs according to the avian or human origin of the protein.

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Section: Resultsmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus

Mettier

Prompt

Bruder

et al. 2023

Viruses

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“…At the same time, PB1F2 could also cause cytochrome c and cardiolipin to separate. We hypothesize that PB1F2 may increase the apoptosis level of immune cells by promoting the dissociation of cytochrome c. The PB1F2 protein has numerous roles via different states and may engage in many functional modes simultaneously or at various stages of virus infection [16,22].…”

Section: Liposome Pulldownmentioning

confidence: 99%

“…PB1F2 proteins expressed in inclusion form can refold in a solution of pH5, but the refolded soluble PB1F2 proteins still behave as structureless. The addition of membrane systems can cause the formation of fibrous aggregation of PB1F2 proteins, which is thought to play a significant role in the destruction of mitochondrial membranes by PB1F2 [15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

PB1F2 from Influenza A Virus Regulates the Interaction between Cytochrome C and Cardiolipin

Wang

2022

Membranes

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PB1F2 is a membrane associated protein encoded by the influenza virus gene in the host. Similar to endogenous pro-apoptotic proteins, it acts on the mitochondria of the host immune cells, inducing apoptosis of the cells. The PB1F2 protein has been demonstrated to facilitate the release of cytochrome c in addition to impairing the integrity of the inner mitochondrial membrane. This investigation focused on how the protein PB1F2 interacted with cardiolipin and cytochrome c. The regulation of PB1F2 on the binding of cytochrome c to cardiolipin in two kinds of in vitro membrane mimics was investigated by biophysical techniques. PB1F2 aids in the dissociation of cytochrome c-cardiolipin complexes in liposomes and nanodiscs. The results provide novel explanations and evidence for how PB1F2 functions as a viral virulence factor by inducing immune cell death.

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Age‐Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1‐F2‐Induced Mitochondrial DNA Release and Activation of cGAS‐STING‐NF‐κB Signaling

Cheung,

Yuen,

Tang

et al. 2024

Journal of Medical Virology

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Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1‐F2 is a pathogenic factor in 15–18‐month‐old BALB/C mice (aged mice) but not in 6–8‐week‐old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1‐F2‐knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2′3′‐cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2′3′‐cGAMP to boost proinflammatory cytokine expression through STING‐NF‐κB signaling. We found that H7N9 PB1‐F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA‐cGAS‐STING‐NF‐κB pathway. H7N9 PB1‐F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V‐dependent electron transport dysfunction, reverse electron transfer‐dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS‐STING‐NF‐κB signaling. PB1‐F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1‐F2‐mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1‐F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human‐adapted descendants. Our findings provide one explanation to age‐dependent pathogenesis of H7N9 infection.

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PB1-F2 amyloid-like fibers correlate with proinflammatory signaling and respiratory distress in influenza-infected mice

Cited by 6 publications

References 57 publications

Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus

Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus

PB1F2 from Influenza A Virus Regulates the Interaction between Cytochrome C and Cardiolipin

Age‐Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1‐F2‐Induced Mitochondrial DNA Release and Activation of cGAS‐STING‐NF‐κB Signaling

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