Unveiling the impact of <scp>GOLM1</scp>/<scp>GP73</scp> on cytokine production in cancer and infectious disease

microRNAs (miRNAs) regulate nearly all physiological processes but our understanding of exactly how they function remains incomplete, particularly in the context of viral infections. Here, we adapt a biochemical method (CLEAR-CLIP) and analysis pipeline to identify targets of miRNAs in lung cells infected with Respiratory syncytial virus (RSV). We show that RSV binds directly to miR-26 and miR-27 through seed pairing and demonstrate that these miRNAs target distinct gene networks associated with cell cycle and metabolism (miR-27) and antiviral immunity (miR-26). Many of the targets are de-repressed upon infection and we show that the miR-27 targets most sensitive to miRNA inhibition are those associated with cell cycle. Finally, we demonstrate that high confidence chimeras map to long noncoding RNAs (lncRNAs) and pseudogenes in transcriptional regulatory regions. We validate that a proportion of miR-27 and Argonaute 2 (AGO2) is nuclear and identify a long non-coding RNA (lncRNA) as a miR-27 target that is linked to transcriptional regulation of nearby genes. This work expands the target networks of miR-26 and miR-27 to include direct interactions with RSV and lncRNAs and implicate these miRNAs in regulation of key genes that impact the viral life cycle associated with cell cycle, metabolism, and antiviral immunity.

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RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

Ressel

Kumar

Bermúdez-Barrientos

et al. 2023

Preprint

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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.

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Unveiling the impact of GOLM1/GP73 on cytokine production in cancer and infectious disease

Cited by 3 publications

References 53 publications

Golgi protein 73 in liver fibrosis

Golgi protein 73 in liver fibrosis

RNA–RNA interactions between respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

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