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Amyloid assemblies of influenza a virus PB1-F2 protein Damage membrane and induce cytotoxicity

Abstract : PB1-F2 is a small accessory protein encoded by an alternative open reading frame in PB1 segments of most influenza A virus. PB1-F2 is involved in virulence by inducing mitochondria-mediated immune cells apoptosis, increasing inflammation, and enhancing predisposition to secondary bacterial infections. Using biophysical approaches we characterized membrane disruptive activity of the full-length PB1-F2 (90 amino acids), its N-terminal domain (52 amino acids), expressed by currently circulating H1N1 viruses, and its C-terminal domain (38 amino acids). Both full-length and N-terminal domain of PB1-F2 are soluble at pH values <= 6, whereas the C-terminal fragment was found soluble only at pH <= 3. All three peptides are intrinsically disordered. At pH >= 7, the C-terminal part of PB1-F2 spontaneously switches to amyloid oligomers, whereas full-length and the N-terminal domain of PB1-F2 aggregate to amorphous structures. When incubated with anionic liposomes at pH 5, full-length and the C-terminal part of PB1-F2 assemble into amyloid structures and disrupt membrane at nanomolar concentrations. PB1-F2 and its C-terminal exhibit no significant antimicrobial activity. When added in the culture medium of mammalian cells, PB1-F2 amorphous aggregates show no cytotoxicity, whereas PB1-F2 pre-assembled into amyloid oligomers or fragmented nanoscaled fibrils was highly cytotoxic. Furthermore, the formation of PB1-F2 amyloid oligomers in infected cells was directly reflected by membrane disruption and cell death as observed in U937 and A549 cells. Altogether our results demonstrate that membrane-lytic activity of PB1-F2 is closely linked to supramolecular organization of the protein.
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Jasmina Vidic, Charles-Adrien Richard, Christine Péchoux, Bruno da Costa, Nicolas Bertho, et al.. Amyloid assemblies of influenza a virus PB1-F2 protein Damage membrane and induce cytotoxicity. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2016, 291 (2), pp.739-751. ⟨10.1074/jbc.M115.652917⟩. ⟨hal-02637618⟩

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