The lncRNA GAS5-encoded micropeptide facilitates influenza virus replication through modulation of the Wnt/β-catenin signaling pathway

 Highlights 

  • •
    Influenza virus infection significantly induces the expression of lncRNA GAS5 via type I/III interferons and IL-6 signal pathways.
  • •
    LncRNA GAS5 can encode a critical micropeptide GAS5-P50 which facilitates influenza virus replication.
  • •
    GAS5-p50 interacts with NOTUM to promote the activation of the Wnt/β-catenin pathway.

ABSTRACT

Long non-coding RNAs (lncRNAs) have been implicated in various cellular processes, including the regulation of gene expression and cellular response to viral infections. Herein, our RNA-seq analysis revealed a significant increase in the expression of an annotated lncRNA, GAS5, following influenza A virus (IAV) infection. Stimulation of cells with type I interferon, type III interferon or IL-6 can also result in upregulation of GAS5 expression. Additionally, overexpression of GAS5 promoted IAV replication, while knockdown of GAS5 decreased viral titers. Notably, we identified a novel 50-amino acid micropeptide encoded by GAS5, named GAS5-P50, through ribosome profiling and mass spectrometry analysis. It was found that overexpression of GAS5-P50 alone could facilitate the replication of IAV; conversely, frameshift mutation-mediated silencing of GAS5-P50 diminished the capacity of GAS5 to promote IAV replication, implying that GAS5-P50 is essential for GAS5-mediated enhancement of viral replication. Moreover, synthetic GAS5-P50 was demonstrated to boost IAV propagation both in vitro and in vivo. Mechanistically, GAS5-P50 interacted with NOTUM, a negative regulator of Wnt signaling, leading to enhanced Wnt/β-catenin pathway activation, which facilitated viral replication. These findings uncover a previously unrecognized function of GAS5 as a proviral lncRNA that encodes a functional micropeptide, which modulates host Wnt/β-catenin signaling to support IAV infection. Our study not only expands the understanding of lncRNA-encoded micropeptides in viral pathogenesis but also highlights GAS5-P50 as a potential target for antiviral intervention.

Read full article for free (open access):
https://www.sciencedirect.com/science/article/pii/S2666517426000143



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