Rani, P and George, B and Sabarishree, V and Biswas, S and Madhurya, V and Pal, A and Rajmani, RS and Das, S (2024) MicroRNA-22-3p displaces critical host factors from the 5� UTR and inhibits the translation of Coxsackievirus B3 RNA. In: Journal of Virology, 98 (2).
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Abstract
Coxsackievirus B3 (CVB3) is known to cause acute myocarditis and pancreatitis in humans. We investigated the microRNAs (miRNAs) that can potentially govern the viral life cycle by binding to the untranslated regions (UTRs) of CVB3 RNA. MicroRNA-22-3p was short-listed, as its potential binding site overlapped with the region crucial for recruiting internal ribosome entry site trans-acting factors (ITAFs) and ribosomes. We demonstrate that miR-22-3p binds CVB3 5� UTR, hinders recruitment of key ITAFs on viral mRNA, disrupts the spatial structure required for ribosome recruitment, and ultimately blocks translation. Likewise, cells lacking miR-22-3p exhibited heightened CVB3 infection compared to wild type, confirming its role in controlling infection. Interestingly, miR-22-3p level was found to be increased at 4 hours post-infection, potentially due to the accumulation of viral 2A protease in the early phase of infection. 2Apro enhances the miR-22-3p level to dislodge the ITAFs from the SD-like sequence, rendering the viral RNA accessible for binding of replication factors to switch to replication. Furthermore, one of the cellular targets of miR-22-3p, protocadherin-1 (PCDH1), was significantly downregulated during CVB3 infection. Partial silencing of PCDH1 reduced viral replication, demonstrating its proviral role. Interestingly, upon CVB3 infection in mice, miR-22-3p level was found to be downregulated only in the small intestine, the primary target organ, indicating its possible role in influencing tissue tropism. It appears miR-22-3p plays a dual role during infection by binding viral RNA to aid its life cycle as a viral strategy and by targeting a proviral protein to restrict viral replication as a host response. IMPORTANCE CVB3 infection is associated with the development of end-stage heart diseases. Lack of effective anti-viral treatments and vaccines for CVB3 necessitates comprehensive understanding of the molecular players during CVB3 infection. miRNAs have emerged as promising targets for anti-viral strategies. Here, we demonstrate that miR-22-3p binds to 5� UTR and inhibits viral RNA translation at the later stage of infection to promote viral RNA replication. Conversely, as host response, it targets PCDH1, a proviral factor, to discourage viral propagation. miR-22-3p also influences CVB3 tissue tropism. Deciphering the multifaced role of miR-22-3p during CVB3 infection unravels the necessary molecular insights, which can be exploited for novel intervening strategies to curb infection and restrict viral pathogenesis. © 2024 American Society for Microbiology. All Rights Reserved.
| Item Type: | Journal Article |
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| Publication: | Journal of Virology |
| Publisher: | American Society for Microbiology |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | host factor; microRNA 22; microRNA 22 3p; protocadherin; protocadherin 1; unclassified drug; virus RNA; antivirus agent; microRNA; MIRN22 microRNA, human; virus RNA, 3' untranslated region; 5' untranslated region; animal experiment; animal model; animal tissue; apoptosis; Article; cell proliferation; cell survival; Coxsackie virus infection; Coxsackievirus B3; Coxsackievirus B3 infection; down regulation; enzyme activity; fluorescence activated cell sorting; gene expression; gene overexpression; genetic transfection; HeLa cell line; human; human cell; immune response; life cycle; luciferase assay; male; mouse; MTT assay; nonhuman; pathogenesis; polymerase chain reaction; RNA immunoprecipitation; RNA isolation; RNA sequence; RNA synthesis; RNA translation; telomeric repeat amplification protocol; tissue tropism; upregulation; Vero cell line; viral plaque assay; virus load; virus replication; Western blotting; 5' untranslated region; animal; Coxsackie virus infection; Enterovirus B; genetics; metabolism, 5' Untranslated Regions; Animals; Antiviral Agents; Coxsackievirus Infections; Enterovirus B, Human; HeLa Cells; Humans; Mice; MicroRNAs; RNA, Viral; Virus Replication |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Microbiology & Cell Biology |
| Date Deposited: | 04 Apr 2024 12:23 |
| Last Modified: | 04 Apr 2024 12:23 |
| URI: | https://eprints.iisc.ac.in/id/eprint/84708 |
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