S100A4 facilitates influenza A virus replication by interacting with M2 in human alveolar epithelial cells
Abstract
Influenza A virus (IAV) replication depends on host cells and is regulated by numerous host factors. Therefore, investigating and understanding the role of these host factors is a significant topic. In this study, we found the IAV replication was attenuated after host factor S100 calcium-binding protein A4 (S100A4) was knocked down with RNAi or knockout with CRISPR/Cas9 gene-editing technology. Conversely, IAV replication was enhanced upon the overexpression in A549 cells. The interaction between S100A4 and the IAV M2 protein was confirmed by co-immunoprecipitation. Meanwhile, confocal microscopy experiment demonstrated that the viral M2 protein co-localized with endogenous S100A4 in IAV-infected A549 cells. Truncation analysis confirmed that amino acids 45–62 of the M2 protein constitute the main interaction region with S100A4. Further study showed that viral entry was reduced after S100A4 deletion. And the polymerase activity was significantly decreased in S100A4-knockout A549 cells compared to that in wild-type A549 cells. The S100A4 overexpression resulted in the downregulation of IFN-β, while the mRNA levels of the interferon-stimulated genes ISG15 and BST2 were also significantly reduced. Therefore, the host factor S100A4 was a positive modulator of IAV replication and was involved in the viral entry, polymerase activity maintenance and innate immune regulation. Collectively, our findings shed new light on the molecular mechanisms governing IAV infection and suggest a previously underexplored avenue for antiviral therapeutic intervention.
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BibTeX
@article{wu2026s100a4,
title = {{S100A4 facilitates influenza A virus replication by interacting with M2 in human alveolar epithelial cells}},
author = {Li Wu and Yingying Tao and Jianing Li and Rui Yang and Jiasheng Song and Jianhong Shu and Yulong He and Huapeng Feng},
journal = {Frontiers in Microbiology},
year = {2026},
month = oct,
doi = {10.3389/fmicb.2026.2011614},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.2011614},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - S100A4 facilitates influenza A virus replication by interacting with M2 in human alveolar epithelial cells
AU - Li Wu
AU - Yingying Tao
AU - Jianing Li
AU - Rui Yang
AU - Jiasheng Song
AU - Jianhong Shu
AU - Yulong He
AU - Huapeng Feng
PY - 2026
DA - 2026/10/29
JO - Frontiers in Microbiology
DO - 10.3389/fmicb.2026.2011614
UR - https://www.frontiersin.org/articles/10.3389/fmicb.2026.2011614
AB - Influenza A virus (IAV) replication depends on host cells and is regulated by numerous host factors. Therefore, investigating and understanding the role of these host factors is a significant topic. In this study, we found the IAV replication was attenuated after host factor S100 calcium-binding protein A4 (S100A4) was knocked down with RNAi or knockout with CRISPR/Cas9 gene-editing technology. Conversely, IAV replication was enhanced upon the overexpression in A549 cells. The interaction between S100A4 and the IAV M2 protein was confirmed by co-immunoprecipitation. Meanwhile, confocal microscopy experiment demonstrated that the viral M2 protein co-localized with endogenous S100A4 in IAV-infected A549 cells. Truncation analysis confirmed that amino acids 45–62 of the M2 protein constitute the main interaction region with S100A4. Further study showed that viral entry was reduced after S100A4 deletion. And the polymerase activity was significantly decreased in S100A4-knockout A549 cells compared to that in wild-type A549 cells. The S100A4 overexpression resulted in the downregulation of IFN-β, while the mRNA levels of the interferon-stimulated genes ISG15 and BST2 were also significantly reduced. Therefore, the host factor S100A4 was a positive modulator of IAV replication and was involved in the viral entry, polymerase activity maintenance and innate immune regulation. Collectively, our findings shed new light on the molecular mechanisms governing IAV infection and suggest a previously underexplored avenue for antiviral therapeutic intervention.
SN - 1664-302X
ER -