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

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

  • Curr Res Microb Sci. 2026 Jan 27:10:100559. doi: 10.1016/j.crmicr.2026.100559.
Xinni Zhou 1 2,  Xiaojuan Chi 1 2 3,  Benqun Peng 1 2,  Ming Gao 1 2,  Ning Li 1 2,  Lu Liu 1 2,  Jie Zeng 1 2,  Yuxin Li 1 2,  Yuzhang Chen 1 2,  Song Wang 1 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
  • 2 Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
  • 3 Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
PMID: 41657547 DOI: 10.1016/j.crmicr.2026.100559
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.

Keywords

GAS5; Influenza A virus; Long non-coding RNA; Micropeptide; Wnt/β-catenin signaling pathway.

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