Abstract
Influenza virus NS2 is well known for its role in viral ribonucleoprotein nuclear export; however, its function has not been fully understood. A recent study showed that NS2 might interact with HIST1H1C (H1C, H1.2). Histones have been found to affect influenza virus replication, such as the H2A, H2B, H3, and H4, but H1 has not been detected. Here, we found that H1C interacts with NS2 via its C-terminal in the nucleus and that H1C affects influenza virus replication. The H1N1 influenza virus replicates better in H1C knockout A549 cells compared to wild-type A549 cells, primarily because of the regulation of H1C on interferon-β (IFN-β). Further studies showed that the H1C phosphorylation mutant (T146A) decreases IFN-β, while H1C methylation mutants (K34A, K187A) increases IFN-β by releasing the nucleosome and promoting IRF3 binding to the IFN-β promoter. Interestingly, NS2 interacts with H1C, which reduces H1C–IRF3 interaction and results in the inhibition of IFN-β enhanced by H1C. In summary, our study reveals a novel function of H1C to regulate IFN-β and uncovers an underlying mechanism, which suggests H1C plays a role in epigenetic regulation. Moreover, our results suggest a novel mechanism for the influenza virus to antagonize the innate immune response by NS2.
Highlights
The influenza virus NS2, whose most important role is to regulate viral ribonucleoprotein nuclear export, affects influenza virus polymerase activity
The plasmids pDsRed-NS2, pDsRed-NS2 was divided into N-terminal (NS2-NT), and pDsRed-NS2-CT were constructed as described above. Small Interfering RNA (siRNA) targeted to H1C was used and the sequence was as follows: 5′-UUUUUCUCCACAUCAUAGCCG-3′; a non-target siRNA was used as negative control, and the sequence was as follows: 5′-UUCUCCGAACGUGUCACGUTT-3′; a siRNA targeted to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as a positive control, and the sequence was as follows: 5′-UGACCUCAACUACAUGGUUTT-3′
To investigate whether NS2 and H1C or its mutants co-localized in the cell, HA-NS2 and Flag-H1C or its mutants were co-expressed in Henrietta Lacks strain of cancer cells (HeLa) cells and IF confocal microscopy was performed as described previously
Summary
The influenza virus NS2, whose most important role is to regulate viral ribonucleoprotein nuclear export, affects influenza virus polymerase activity. Its function has not been fully understood, and in-depth studies are needed to further elucidate its functions and the mechanism. A recent study on the influenza A virus NS2 demonstrated that it potentially interacts with host factors, including HIS1H1C (H1C, H1.2) [1]. Hoeksema et al found that histones H3 and H4 neutralize influenza virus in a more robust manner compared to H2A and H2B [2], while histone H1 has not been detected. These findings indicate that H1C may affect influenza virus replication
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