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Prediction of human protein interactome of dengue virus non-structural protein 5 (NS5) and its downstream immunological implications

Abstract

The non-structural protein 5 (NS5) is the most conserved protein among flaviviruses, a family that includes the dengue virus. It functions both as an RNA-dependent RNA polymerase and an RNA-methyltransferase and is therefore essential for the replication of viral RNA. The discovery that dengue virus NS5 protein (DENV-NS5) can also localize to the nucleus has resulted in renewed interest in its potential roles at the host-virus interface. In this study, we have used two complementary computational approaches in parallel – one based on linear motifs (ELM) and another based on tertiary structure of the protein (DALI) – to predict the host proteins that DENV-NS5 might interact with. Of the 42 human proteins predicted by both these methods, 34 are novel. Pathway analysis of these 42 human proteins shows that they are involved in key host cellular processes related to cell cycle regulation, proliferation, protein degradation, apoptosis, and immune responses. A focused analysis of transcription factors that directly interact with the predicted DENV-NS5 interacting proteins was performed, followed by the identification of downstream genes that are differentially expressed after dengue infection using previously published RNA-seq data. Our study provides unique insights into the DENV-NS5 interaction network and delineates mechanisms whereby DENV-NS5 could impact the host-virus interface. The novel interactors identified in this study could be potentially targeted by NS5 to modulate the host cellular environment in general, and the immune response in particular, thereby extending the role of DENV-NS5 beyond its known enzymatic functions.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

We would like to thank Dr. Sakshi Chaudhary (ICGEB, New Delhi) and Love Panchariya (ICGEB, New Delhi) for their valuable inputs at the time of manuscript revision.

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The authors did not receive support from any organization for the submitted work.

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Conceptualization and design of pipeline was done by JS and PB. Data curation and analysis was done by PB. RNA-seq data curation and analysis was done by PB. Figures were made by PB and PB. PB wrote the first draft. Rewriting, reviewing and editing were done by PB, MKK, AC and RS.

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Correspondence to Priya Bhatnagar, Anmol Chandele or Ramakrishnan Sitaraman.

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Bhatnagar, P., Bajpai, P., Shrinet, J. et al. Prediction of human protein interactome of dengue virus non-structural protein 5 (NS5) and its downstream immunological implications. 3 Biotech 13, 180 (2023). https://doi.org/10.1007/s13205-023-03569-0

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