Preprint Respiratory syncytial virus directly binds miR-26, miR-27, and let-7 to de-repress gene targets through canonical and non-canonical mechanisms, 2023

[SNT Gatchaman]

Respiratory syncytial virus directly binds miR-26, miR-27, and let-7 to de-repress gene targets through canonical and non-canonical mechanisms
Sarah Ressel; Sujai Kumar; Jose Roberto Bermudez-Barrientos; Katrina Gordon; Julia Lane; Jin Wu; Cei Abreu-Goodger; Jurgen Schwarze; Amy H Buck

Specific viruses can sequester or inhibit miRNAs through direct RNA-RNA interactions to enable their life cycle, but we still lack comprehensive understanding of the existence and functions of such interactions in respiratory virus infections.

Here we optimise the CLEAR-CLIP protocol in A549 cells and show that Respiratory syncytial virus (RSV) directly binds miR-26, miR-27, and let-7. We show a significant global up-regulation of miR-26 targets upon RSV infection as well as up-regulation of miR-27 targets involved in cell cycle regulation and immune signalling. Through genome analysis of miRNA-target reads we further show that pseudogenes which overlap transcriptional regulatory regions are functional miRNA targets. We identify and validate an interaction between miR-27 and a pseudogene-derived lncRNA that overlaps an enhancer and show that this interaction regulates expression of Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1).

This work demonstrates that RSV directly interacts with host miRNAs to de-regulate host gene expression and provides biochemical support for the ability of miRNAs to directly regulate gene transcription linked to immune signalling.

Link | PDF (Preprint: BioRxiv)

 

[SNT Gatchaman]

A couple of introductory and concluding quotes —

Viruses have evolved many tactics to manipulate host cells to facilitate their life cycles, but we still lack a comprehensive understanding of all the molecules and mechanisms involved. Over the last two decades, various studies have revealed the ability of specific viruses to interact with cellular miRNAs through direct RNA-RNA interactions.

To date no miRNA- virus interactions have been directly identified in respiratory viruses

In this study we have focussed on miR-27 targets, however the interaction of RSV with miR-26 and let-7 are also intriguing and merit further attention. miR-26 has previously been reported to regulate antiviral immunity in several different viral infections and has been implicated in the inhibition of TLR4 signalling in RSV infection. Here we demonstrate that RSV has evolved to directly inhibit the functional activity of this miRNA, re-enforcing a central role of miR-26 in antiviral signalling.

In conclusion, this study adds RSV to a growing list of viruses known to directly interact with miRNAs during their life cycles and highlights pseudogenes as a class of miRNA targets that can mediate transcriptional regulation.