A novel influenza A virus mitochondrial protein that induces cell death

Abstract

While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.

Potential killers exposed: tracking endogenous influenza‐specific CD8+ T cells

“…Recombinant viruses, WT HKx31 and mutant HKx31(–NP –PA –F2) (TKO), and HKx31(–NP –PA –F2 –PB1 –NS2) (QKO) were generated, using the eight‐plasmid reverse genetics system described previously for the mutation of the D b NP 366–374 and D b PA 224–233 epitopes 47, 48. In the TKO viruses, the WT D b PB1‐F2 62–70 epitope (LSLRNPILV was changed to LSLRQPILV 49. In the QKO virus, the WT K b PB1 703–711 epitope (SSYRRVPGI) was changed to SSFRRVPGI, and the WT K b NS2 114–121 epitope (RTFSFQLI) was changed to RTFSAQLI.…”

Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan

“…Compared to the full-length PB1-F2, this protein is unlikely to be functional. As a pro-apoptotic factor, PB1-F2 plays an important role in viral pathogenicity both in vitro and in vivo (Chen et al, 2001;Zamarinet et al, 2006). In addition, PB1-F2 increases susceptibility to secondary bacterial pneumonia in mice (McAuley et al, 2007).…”

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K+ permeability: A new member of the viroporin family?

“…Segments A-D of the protein represent, respectively, the amphipathic a-helical domain, the transmembrane domain, the hinge region and the C-terminal beta sheet hairpin. Panel C also shows a more detailed helical wheel model of the amphipathic a-helical domain of p13 (amino acids [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Panel C does not indicate the matrix and intermembrane space faces of the inner membrane, as the topology of p13 has not been defined.…”

“…Immuno-electron microscopy and sub-mitochondrial fractionation experiments demonstrated that the majority of p13 is inserted as an integral membrane protein in the inner mitochondrial membrane [6]. The mitochondrial targeting of p13 is directed by an atypical mitochondrial targeting sequence (MTS) formed by 10 amino-proximal residues (amino acids [21][22][23][24][25][26][27][28][29][30] that are contained within the a-helix described above [7], with four arginines in the MTS conferring amphipathic properties to the helix. In contrast to canonic MTSs, the targeting signal of p13 is not cleaved upon import into mitochondria [7].…”

“…PB1-F2 localizes in the nucleus, cytosol and mitochondria of infected cells. PB1-F2 is conserved in most mammalian and avian IAV isolates as a 78-90 amino acid protein, while it is not present in the influenza B virus strains [29]. PB1-F2 contains an amphipathic helix spanning residues 69-83, is targeted to mitochondria and triggers cell death, all features which are reminiscent of HTLV-1 p13 [29].…”