tetano
Editor, Senior Moderator
Poult Sci
. 2026 Jan 28;105(4):106529.
doi: 10.1016/j.psj.2026.106529. Online ahead of print.
The host RNA helicase DDX6 restricts avian influenza virus replication by targeting viral NP and modulating ISG15
Xiaolong Lu[SUP] 1 [/SUP], Chenyu Lu[SUP] 2 [/SUP], Mengyang He[SUP] 2 [/SUP], Xinen Tang[SUP] 2 [/SUP], Zhuxing Ji[SUP] 2 [/SUP], Hongqi Wu[SUP] 3 [/SUP], Kaituo Liu[SUP] 1 [/SUP], Wenhao Yang[SUP] 4 [/SUP], Yu Chen[SUP] 4 [/SUP], Ruyi Gao[SUP] 4 [/SUP], Jiao Hu[SUP] 4 [/SUP], Min Gu[SUP] 4 [/SUP], Shunlin Hu[SUP] 4 [/SUP], Xiaowen Liu[SUP] 4 [/SUP], Xiaoquan Wang[SUP] 5 [/SUP], Xiufan Liu[SUP] 4 [/SUP]
Affiliations
The H7N9 subtype of avian influenza virus (AIV) poses a significant and ongoing threat to public health. As a critical structural and functional component, the viral nucleoprotein (NP) is abundantly expressed during the early stages of AIV replication; however, its interactions with host proteins and their functional consequences remain largely uncharacterized. This study aimed to identify the NP-host interaction and elucidate the mechanisms by which these interactions modulate AIV replication. Here, we employed mass spectrometry and identified the DEAD-box helicase 6 (DDX6) as a novel NP-interacting partner, an association found to be regulated by an interferon-stimulated gene (ISG15). The NP-DDX6 interaction was robustly validated by co-immunoprecipitation, immunofluorescence co-localization, bimolecular fluorescence complementation, and molecular docking assays. Functional investigations revealed that DDX6 acts as a potent negative regulator of AIV replication. Mechanistically, DDX6 not only impaired the nuclear import of NP and suppressed viral polymerase activity, but also stimulated the production of interferon (IFN)-α/β. This IFN-I induction, in turn, triggers the expression of downstream antiviral effectors such as ISG15. Furthermore, we uncovered that DDX6 fine-tunes this pathway by playing a sophisticated dual regulatory role: it enhances the pool of free, antiviral ISG15 monomers while concurrently reducing ISGylation via two deubiquitinases (USP16/USP18). Collectively, these findings not only establish DDX6 as a crucial host factor with potent antiviral activity but also enrich our understanding of host-virus interaction networks.
Keywords: AIV; DDX6; H7N9; ISG15; NP.
. 2026 Jan 28;105(4):106529.
doi: 10.1016/j.psj.2026.106529. Online ahead of print.
The host RNA helicase DDX6 restricts avian influenza virus replication by targeting viral NP and modulating ISG15
Xiaolong Lu[SUP] 1 [/SUP], Chenyu Lu[SUP] 2 [/SUP], Mengyang He[SUP] 2 [/SUP], Xinen Tang[SUP] 2 [/SUP], Zhuxing Ji[SUP] 2 [/SUP], Hongqi Wu[SUP] 3 [/SUP], Kaituo Liu[SUP] 1 [/SUP], Wenhao Yang[SUP] 4 [/SUP], Yu Chen[SUP] 4 [/SUP], Ruyi Gao[SUP] 4 [/SUP], Jiao Hu[SUP] 4 [/SUP], Min Gu[SUP] 4 [/SUP], Shunlin Hu[SUP] 4 [/SUP], Xiaowen Liu[SUP] 4 [/SUP], Xiaoquan Wang[SUP] 5 [/SUP], Xiufan Liu[SUP] 4 [/SUP]
Affiliations
- PMID: 41633077
- DOI: 10.1016/j.psj.2026.106529
The H7N9 subtype of avian influenza virus (AIV) poses a significant and ongoing threat to public health. As a critical structural and functional component, the viral nucleoprotein (NP) is abundantly expressed during the early stages of AIV replication; however, its interactions with host proteins and their functional consequences remain largely uncharacterized. This study aimed to identify the NP-host interaction and elucidate the mechanisms by which these interactions modulate AIV replication. Here, we employed mass spectrometry and identified the DEAD-box helicase 6 (DDX6) as a novel NP-interacting partner, an association found to be regulated by an interferon-stimulated gene (ISG15). The NP-DDX6 interaction was robustly validated by co-immunoprecipitation, immunofluorescence co-localization, bimolecular fluorescence complementation, and molecular docking assays. Functional investigations revealed that DDX6 acts as a potent negative regulator of AIV replication. Mechanistically, DDX6 not only impaired the nuclear import of NP and suppressed viral polymerase activity, but also stimulated the production of interferon (IFN)-α/β. This IFN-I induction, in turn, triggers the expression of downstream antiviral effectors such as ISG15. Furthermore, we uncovered that DDX6 fine-tunes this pathway by playing a sophisticated dual regulatory role: it enhances the pool of free, antiviral ISG15 monomers while concurrently reducing ISGylation via two deubiquitinases (USP16/USP18). Collectively, these findings not only establish DDX6 as a crucial host factor with potent antiviral activity but also enrich our understanding of host-virus interaction networks.
Keywords: AIV; DDX6; H7N9; ISG15; NP.