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Review
. 2024 Jan 23;98(1):e0119223.
doi: 10.1128/jvi.01192-23. Epub 2024 Jan 4.

Unveiling the role of host kinases at different steps of influenza A virus life cycle

Affiliations
Review

Unveiling the role of host kinases at different steps of influenza A virus life cycle

Soumik Dey et al. J Virol. .

Abstract

Influenza viruses remain a major public health concern causing contagious respiratory illnesses that result in around 290,000-650,000 global deaths every year. Their ability to constantly evolve through antigenic shifts and drifts leads to the emergence of newer strains and resistance to existing drugs and vaccines. To combat this, there is a critical need for novel antiviral drugs through the introduction of host-targeted therapeutics. Influenza viruses encode only 14 gene products that get extensively modified through phosphorylation by a diverse array of host kinases. Reversible phosphorylation at serine, threonine, or tyrosine residues dynamically regulates the structure, function, and subcellular localization of viral proteins at different stages of their life cycle. In addition, kinases influence a plethora of signaling pathways that also regulate virus propagation by modulating the host cell environment thus establishing a critical virus-host relationship that is indispensable for executing successful infection. This dependence on host kinases opens up exciting possibilities for developing kinase inhibitors as next-generation anti-influenza therapy. To fully capitalize on this potential, extensive mapping of the influenza virus-host kinase interaction network is essential. The key focus of this review is to outline the molecular mechanisms by which host kinases regulate different steps of the influenza A virus life cycle, starting from attachment-entry to assembly-budding. By assessing the contributions of different host kinases and their specific phosphorylation events during the virus life cycle, we aim to develop a holistic overview of the virus-host kinase interaction network that may shed light on potential targets for novel antiviral interventions.

Keywords: ERK; MAP kinase; PKC; RNP assembly; RNP export; host kinases; influenza; viral transcription and replication.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
Cartoon representation of influenza virus architecture. The surface of the virion particle is decorated with HA trimers and NA tetramers and M2 ion channels anchored into the lipid bilayer membrane. The M1 protein forms inner matrix layer beneath the envelope. The virion core consists of eight RNP particles (left). RNPs are composed of genomic RNA enwrapped with NP and the heterotrimeric RNA polymerase (RdRp) consisting of PB1, PB2, and PA proteins (right).
Fig 2
Fig 2
Different phases of influenza virus life cycle and involvement of host kinases. (1) Attachment of virion particle with the host cell surface receptor. (2) Receptor-mediated endocytosis. (3) Endosomes are trafficked through the cytoplasm. (4) Fusion of endosomal membrane and viral envelope releases vRNPs into cytoplasm, which are then transported to the nucleus. (5) Imported vRNPs perform primary transcription to produce viral mRNAs. (6) mRNAs are transported from the nucleus to the cytoplasm. (7a) mRNAs encoding viral polymerase proteins (PB1, PB2, PA, NP, M1, and NEP) get translated into the cytoplasm. (7b) mRNAs encoding viral membrane proteins (HA, NA, and M2) get translated by the endoplasmic reticulum-Golgi network. (8a) Viral non-membranous proteins are transported back to the nucleus. (8b) Membrane proteins are trafficked to the plasma membrane. (9a) vRNPs perform cRNA replication in the presence of newly synthesized proteins thus forming cRNPs. (9b) Positive-sense cRNPs get copied to negative-sense vRNPs. (10) vRNPs are exported out of the nucleus with the help of M1 and NEP proteins. (11) vRNPs are transported to the plasma membrane by Rab11 vesicles. (12) Eight vRNPs are packed into the new virion particle and bud out of the cell by snatching a portion of the host cell plasma membrane already decorated with viral membrane proteins. Host kinases involved in various phases of the life cycle are highlighted in different color schemes as depicted. The entire schematic is oversimplified where the involvement of other host factors is excluded.
Fig 3
Fig 3
Phospho-regulation of NP oligomerization. Monomeric NP structure (PDB: 2iqh) consists of a head and a body domain and a tail loop extended outward from the core of the protein. Individual NP protomers interact through salt bridge interaction between the tail loop (E339) of one and the groove (R416) of the other. PKCδ-mediated reversible phosphorylation at S407 in the tail loop and S165 in the binding groove sterically inhibits tail loop-groove interaction and thus phospho-modulates NP oligomerization, RNP assembly, and genomic RNA replication. This figure is adapted from Mondal et al. (73).
Fig 4
Fig 4
Mechanism of vRNP export and involvement of host kinases. Y132 and T108 phosphorylation regulates nuclear entry of M1 protein. MEK-ERK-RSK1-mediated phosphorylation at S269 and S392 enables NP to interact with M1 and thereby facilitates Crm1-Ran-GTP-dependent export of vRNPs through the intermediacy of NEP. However, NEP interacts with viral polymerase for facilitating this way of transport, not shown here. Specific NP phosphorylation at Y78 and Y296 inhibits its interaction with Crm1, thereby inhibiting Crm1-dependent Ran-GTP-independent export of vRNPs. TrkA and Sphk promote Crm1-mediated export of vRNPs. Crm1-independent export of vRNPs is also inhibited by specific NP phosphorylation at T188 by unknown kinases.

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References

    1. Ramazi S, Zahiri J. 2021. Post-translational modifications in proteins: resources, tools and prediction methods. Database (Oxford) 2021:baab012. doi:10.1093/database/baab012 - DOI - PMC - PubMed
    1. Mann M, Jensen ON. 2003. Proteomic analysis of post-translational modifications. Nat Biotechnol 21:255–261. doi:10.1038/nbt0303-255 - DOI - PubMed
    1. Cheng H-C, Qi RZ, Paudel H, Zhu H-J. 2011. Regulation and function of protein kinases and phosphatases. Enzyme Res 2011:794089. doi:10.4061/2011/794089 - DOI - PMC - PubMed
    1. Ubersax JA, Ferrell JE. 2007. Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol 8:530–541. doi:10.1038/nrm2203 - DOI - PubMed
    1. Kumar R, Mehta D, Mishra N, Nayak D, Sunil S. 2020. Role of host-mediated post-translational modifications (PTMs) in RNA virus pathogenesis. Int J Mol Sci 22:323. doi:10.3390/ijms22010323 - DOI - PMC - PubMed

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