Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1.
The influenza virus PB1-F2 is an 87-amino acid mitochondrial protein that previously has been shown to induce cell death, although the mechanism of apoptosis induction has remained unclear. In the process of characterizing its mechanism of action we found that the viral PB1-F2 protein sensitizes cel...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2005-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.0010004 |
| _version_ | 1818582015887278080 |
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| author | Dmitriy Zamarin Adolfo García-Sastre Xiaoyao Xiao Rong Wang Peter Palese |
| author_facet | Dmitriy Zamarin Adolfo García-Sastre Xiaoyao Xiao Rong Wang Peter Palese |
| author_sort | Dmitriy Zamarin |
| collection | DOAJ |
| description | The influenza virus PB1-F2 is an 87-amino acid mitochondrial protein that previously has been shown to induce cell death, although the mechanism of apoptosis induction has remained unclear. In the process of characterizing its mechanism of action we found that the viral PB1-F2 protein sensitizes cells to apoptotic stimuli such as tumor necrosis factor alpha, as demonstrated by increased cleavage of caspase 3 substrates in PB1-F2-expressing cells. Moreover, treatment of purified mouse liver mitochondria with recombinant PB1-F2 protein resulted in cytochrome c release, loss of the mitochondrial membrane potential, and enhancement of tBid-induced mitochondrial permeabilization, suggesting a possible mechanism for the observed cellular sensitization to apoptosis. Using glutathione-S-transferase pulldowns with subsequent mass spectrometric analysis, we identified the mitochondrial interactors of the PB1-F2 protein and showed that the viral protein uniquely interacts with the inner mitochondrial membrane adenine nucleotide translocator 3 and the outer mitochondrial membrane voltage-dependent anion channel 1, both of which are implicated in the mitochondrial permeability transition during apoptosis. Consistent with this interaction, blockers of the permeability transition pore complex (PTPC) inhibited PB1-F2-induced mitochondrial permeabilization. Based on our findings, we propose a model whereby the proapoptotic PB1-F2 protein acts through the mitochondrial PTPC and may play a role in the down-regulation of the host immune response to infection. |
| first_indexed | 2024-12-16T07:42:40Z |
| format | Article |
| id | doaj.art-3194351421344ebda8e9f63e4d64e5a1 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-16T07:42:40Z |
| publishDate | 2005-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-3194351421344ebda8e9f63e4d64e5a12022-12-21T22:39:03ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742005-09-0111e410.1371/journal.ppat.0010004Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1.Dmitriy ZamarinAdolfo García-SastreXiaoyao XiaoRong WangPeter PaleseThe influenza virus PB1-F2 is an 87-amino acid mitochondrial protein that previously has been shown to induce cell death, although the mechanism of apoptosis induction has remained unclear. In the process of characterizing its mechanism of action we found that the viral PB1-F2 protein sensitizes cells to apoptotic stimuli such as tumor necrosis factor alpha, as demonstrated by increased cleavage of caspase 3 substrates in PB1-F2-expressing cells. Moreover, treatment of purified mouse liver mitochondria with recombinant PB1-F2 protein resulted in cytochrome c release, loss of the mitochondrial membrane potential, and enhancement of tBid-induced mitochondrial permeabilization, suggesting a possible mechanism for the observed cellular sensitization to apoptosis. Using glutathione-S-transferase pulldowns with subsequent mass spectrometric analysis, we identified the mitochondrial interactors of the PB1-F2 protein and showed that the viral protein uniquely interacts with the inner mitochondrial membrane adenine nucleotide translocator 3 and the outer mitochondrial membrane voltage-dependent anion channel 1, both of which are implicated in the mitochondrial permeability transition during apoptosis. Consistent with this interaction, blockers of the permeability transition pore complex (PTPC) inhibited PB1-F2-induced mitochondrial permeabilization. Based on our findings, we propose a model whereby the proapoptotic PB1-F2 protein acts through the mitochondrial PTPC and may play a role in the down-regulation of the host immune response to infection.https://doi.org/10.1371/journal.ppat.0010004 |
| spellingShingle | Dmitriy Zamarin Adolfo García-Sastre Xiaoyao Xiao Rong Wang Peter Palese Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathogens |
| title | Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. |
| title_full | Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. |
| title_fullStr | Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. |
| title_full_unstemmed | Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. |
| title_short | Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. |
| title_sort | influenza virus pb1 f2 protein induces cell death through mitochondrial ant3 and vdac1 |
| url | https://doi.org/10.1371/journal.ppat.0010004 |
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