A multi-faceted effector: The RNA-dependent RNA polymerase of dengue virus

The non-structural protein 5 (NS5) of dengue virus may be involved in host-pathogen interactions in addition to its core, essential functions - replicating and capping the viral RNA.
Published in Microbiology
A multi-faceted effector: The RNA-dependent RNA polymerase of dengue virus
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Prediction of human protein interactome of dengue virus non-structural protein 5 (NS5) and its downstream immunological implications - 3 Biotech

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.

Age cannot wither her, nor custom stale

Her infinite variety.

                                    - William Shakespeare, Antony and Cleopatra, Act II, scene 2

The dengue virus (DENV) possesses an RNA-dependent RNA polymerase (NS5) that replicates its RNA genome besides capping the nascent RNA to enhance stability.  Given its centrality to the propagation of DENV, it presents an attractive target for drug development and is also known to be highly immunogenic in humans.  However, replication of the viral genome is by no means its sole function; it is also likely involved in mediating virus-host interactions, specifically by modulating host immune responses.  The moonlighting functions of NS5 have been known for some time1-3, as has its nuclear localization in the case of DENV serotypes 2 & 44-6.   Many research groups have sought to determine the human proteins that interact with NS5 using a variety of experimental approaches, which have been compiled in a review we published in 20217.

Given these antecedents, it was tempting to for us to make an attempt to computationally predict interactions with human proteins that could form the basis of testable hypotheses leading to a better understanding of the mechanisms underlying observed immunological effects of dengue infection.  In our work published in 3 Biotech we have tried to make precisely such predictions starting with a conservative set of 42 human interactors that we identified8.  Pathway analysis enabled us to focus on the subsequent interactors that were immunologically relevant.  While predictions and speculations may seem trite, prior work, particularly the online availability of raw experimental data from RNA-seq experiments enabled us to validate some of our predictions.  In other words, some of our predictions have already been borne out by experiment, giving us hope that other inferences we have made would be of value as well for other researchers, particularly immunologists.         

DENV belongs to the family Flaviviridae

Note:  Poster image reproduced from Fig. 1 of Bhatnagar et al8.  

References:

1.  Ashour et al. (2009).  NS5 of Dengue Virus Mediates STAT2 Binding and Degradation. J Virol 83(11):5408 - 5418.  doi: 10.1128/jvi.02188-08.

2.  Petit et al. (2021).  Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes. PLOS Pathogens 17(11): e1010100. doi: 10.1371/journal.ppat.1010100 

3.  Ledesma et al. (2023).  Dengue virus NS5 degrades ERC1 during infection to antagonize NF-kB activation.  Proc Natl Acad Sci USA 120(23):e2220005120.  doi: 10.1073/pnas.2220005120 

4.  R. Bulich, J. G. Aaskov (1992).  Nuclear localization of dengue 2 virus core protein detected with monoclonal antibodies.  Microbiology 73(11): 2999-3003.  doi: 10.1099/0022-1317-73-11-2999.

5.  Tadano et al. (1989).  Detection of Dengue 4 Virus Core Protein in the Nucleus. I. A Monoclonal Antibody to Dengue 4 Virus Reacts with the Antigen in the Nucleus and Cytoplasm.  Microbiology 70(6): 1409-15.  doi: 10.1099/0022-1317-70-6-1409.

6.  Makino et al. (1989).  Detection of Dengue 4 Virus Core Protein in the Nucleus. II. Antibody against Dengue 4 Core Protein Produced by a Recombinant Baculovirus Reacts with the Antigen in the Nucleus.  Microbiology 70(6): 1417-25. doi: 10.1099/0022-1317-70-6-1417. 

7.  Bhatnagar et al. (2021). Dengue Virus Non-Structural Protein 5 as a Versatile, Multi-Functional Effector in Host–Pathogen Interactions. Front Cell Infect Microbiol 11:574067. doi: 10.3389/fcimb.2021.574067.

8.  Bhatnagar et al. (2023). Prediction of human protein interactome of dengue virus non-structural protein 5 (NS5) and its downstream immunological implications. 3 Biotech 13(6): 180. doi: 10.1007/s13205-023-03569-0

9.  Grant et al. (2016). Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling.  Cell Host Microbe 19(6): 882-890. doi: 10.1016/j.chom.2016.05.009.

Disclaimer:  The opinions expressed herein do not represent the views of the TERI School of Advanced Studies or TERI.

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  • 3 Biotech 3 Biotech

    This is a hybrid journal that publishes results of the latest research related to the study and application of biotechnology to Medicine and Biomedical Sciences, Agriculture and the Environment.