tetano
Editor, Senior Moderator
Curr Res Microb Sci
. 2026 Jan 27:10:100559.
doi: 10.1016/j.crmicr.2026.100559. eCollection 2026.
The lncRNA GAS5-encoded micropeptide facilitates influenza virus replication through modulation of the Wnt/β-catenin signaling pathway
Xinni Zhou[SUP] 1 2 [/SUP], Xiaojuan Chi[SUP] 1 2 3 [/SUP], Benqun Peng[SUP] 1 2 [/SUP], Ming Gao[SUP] 1 2 [/SUP], Ning Li[SUP] 1 2 [/SUP], Lu Liu[SUP] 1 2 [/SUP], Jie Zeng[SUP] 1 2 [/SUP], Yuxin Li[SUP] 1 2 [/SUP], Yuzhang Chen[SUP] 1 2 [/SUP], Song Wang[SUP] 1 2 3 [/SUP]
Affiliations
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.
Keywords: GAS5; Influenza A virus; Long non-coding RNA; Micropeptide; Wnt/β-catenin signaling pathway.
. 2026 Jan 27:10:100559.
doi: 10.1016/j.crmicr.2026.100559. eCollection 2026.
The lncRNA GAS5-encoded micropeptide facilitates influenza virus replication through modulation of the Wnt/β-catenin signaling pathway
Xinni Zhou[SUP] 1 2 [/SUP], Xiaojuan Chi[SUP] 1 2 3 [/SUP], Benqun Peng[SUP] 1 2 [/SUP], Ming Gao[SUP] 1 2 [/SUP], Ning Li[SUP] 1 2 [/SUP], Lu Liu[SUP] 1 2 [/SUP], Jie Zeng[SUP] 1 2 [/SUP], Yuxin Li[SUP] 1 2 [/SUP], Yuzhang Chen[SUP] 1 2 [/SUP], Song Wang[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 41657547
- PMCID: PMC12874442
- DOI: 10.1016/j.crmicr.2026.100559
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.
Keywords: GAS5; Influenza A virus; Long non-coding RNA; Micropeptide; Wnt/β-catenin signaling pathway.