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Phosphoproteomics to characterize host response during influenza A virus infection of human macrophages

(2016) MOLECULAR & CELLULAR PROTEOMICS. 15(10). p.3203-3219
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Abstract
Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses. To this end, we characterized the phosphoproteome of influenza A virus infected primary human macrophages to elucidate the intracellular signaling pathways and critical host factors activated upon influenza infection. We identified 1675 phosphoproteins, 4004 phosphopeptides and 4146 nonredundant phosphosites. The phosphorylation of 1113 proteins (66%) was regulated upon infection, highlighting the importance of such global phosphoproteomic profiling in primary cells. Notably, 285 of the identified phosphorylation sites have not been previously described in publicly available phosphorylation databases, despite many published large-scale phosphoproteome studies using human and mouse cell lines. Systematic bioinformatics analysis of the phosphoproteome data indicated that the phosphorylation of proteins involved in the ubiquitin/proteasome pathway (such as TRIM22 and TRIM25) and antiviral responses (such as MAVS) changed in infected macrophages. Proteins known to play roles in small GTPase-, mitogen-activated protein kinase-, and cyclin-dependent kinase-signaling were also regulated by phosphorylation upon infection. In particular, the influenza infection had a major influence on the phosphorylation profiles of a large number of cyclin-dependent kinase substrates. Functional studies using cyclin-dependent kinase inhibitors showed that the cyclin-dependent kinase activity is required for efficient viral replication and for activation of the host antiviral responses. In addition, we show that cyclin-dependent kinase inhibitors protect IAV-infected mice from death. In conclusion, we provide the first comprehensive phosphoproteome characterization of influenza A virus infection in primary human macrophages, and provide evidence that cyclin-dependent kinases represent potential therapeutic targets for more effective treatment of influenza infections.
Keywords
INDUCED-APOPTOSIS, UBIQUITIN LIGASE, QUANTITATIVE PHOSPHOPROTEOMICS, ANTIVIRAL ACTIVITY, RIG-I, TRANSCRIPTION FACTORS, NS1 PROTEIN, RNA RECOGNITION PATHWAY, DEPENDENT KINASE INHIBITORS, REPLICATION

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Citation

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Chicago
Söderholm, Sandra, Denis E Kainov, Tiina Öhman, Oxana V Denisova, Bert Schepens, Evgeny Kulesskiy, Susumu Y Imanishi, et al. 2016. “Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages.” Molecular & Cellular Proteomics 15 (10): 3203–3219.
APA
Söderholm, S., Kainov, D. E., Öhman, T., Denisova, O. V., Schepens, B., Kulesskiy, E., Imanishi, S. Y., et al. (2016). Phosphoproteomics to characterize host response during influenza A virus infection of human macrophages. MOLECULAR & CELLULAR PROTEOMICS, 15(10), 3203–3219.
Vancouver
1.
Söderholm S, Kainov DE, Öhman T, Denisova OV, Schepens B, Kulesskiy E, et al. Phosphoproteomics to characterize host response during influenza A virus infection of human macrophages. MOLECULAR & CELLULAR PROTEOMICS. 2016;15(10):3203–19.
MLA
Söderholm, Sandra et al. “Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages.” MOLECULAR & CELLULAR PROTEOMICS 15.10 (2016): 3203–3219. Print.
@article{8201611,
  abstract     = {Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses. To this end, we characterized the phosphoproteome of influenza A virus infected primary human macrophages to elucidate the intracellular signaling pathways and critical host factors activated upon influenza infection. We identified 1675 phosphoproteins, 4004 phosphopeptides and 4146 nonredundant phosphosites. The phosphorylation of 1113 proteins (66%) was regulated upon infection, highlighting the importance of such global phosphoproteomic profiling in primary cells. Notably, 285 of the identified phosphorylation sites have not been previously described in publicly available phosphorylation databases, despite many published large-scale phosphoproteome studies using human and mouse cell lines. Systematic bioinformatics analysis of the phosphoproteome data indicated that the phosphorylation of proteins involved in the ubiquitin/proteasome pathway (such as TRIM22 and TRIM25) and antiviral responses (such as MAVS) changed in infected macrophages. Proteins known to play roles in small GTPase-, mitogen-activated protein kinase-, and cyclin-dependent kinase-signaling were also regulated by phosphorylation upon infection. In particular, the influenza infection had a major influence on the phosphorylation profiles of a large number of cyclin-dependent kinase substrates. Functional studies using cyclin-dependent kinase inhibitors showed that the cyclin-dependent kinase activity is required for efficient viral replication and for activation of the host antiviral responses. In addition, we show that cyclin-dependent kinase inhibitors protect IAV-infected mice from death. In conclusion, we provide the first comprehensive phosphoproteome characterization of influenza A virus infection in primary human macrophages, and provide evidence that cyclin-dependent kinases represent potential therapeutic targets for more effective treatment of influenza infections.},
  author       = {Söderholm, Sandra and Kainov, Denis E and Öhman, Tiina and Denisova, Oxana V and Schepens, Bert and Kulesskiy, Evgeny and Imanishi, Susumu Y and Corthals, Garry and Hintsanen, Petteri and Aittokallio, Tero and Saelens, Xavier and Matikainen, Sampsa and Nyman, Tuula A},
  issn         = {1535-9476},
  journal      = {MOLECULAR & CELLULAR PROTEOMICS},
  keywords     = {INDUCED-APOPTOSIS,UBIQUITIN LIGASE,QUANTITATIVE PHOSPHOPROTEOMICS,ANTIVIRAL ACTIVITY,RIG-I,TRANSCRIPTION FACTORS,NS1 PROTEIN,RNA RECOGNITION PATHWAY,DEPENDENT KINASE INHIBITORS,REPLICATION},
  language     = {eng},
  number       = {10},
  pages        = {3203--3219},
  title        = {Phosphoproteomics to characterize host response during influenza A virus infection of human macrophages},
  url          = {http://dx.doi.org/10.1074/mcp.M116.057984},
  volume       = {15},
  year         = {2016},
}

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