[Influenza A virus-induced expression of ZFAS1 is regulated by type Ⅰ interferon and significantly suppresses the viral replication].

To investigate the roles of long non-coding RNAs (lncRNAs) and potential micropeptides encoded by these lncRNAs in influenza A virus (IAV) replication, we analyzed the data obtained from RNA-seq and Ribo-seq. We found that the lncRNA zinc finger antisense 1 (ZFAS1) was significantly up-regulated by IAV infection. This finding was confirmed by in vitro experiments, which showed that IAV infection caused a significant increase in the expression of ZFAS1, with the effect exhibiting a dose- and time-dependent relationship in response to the viral infection. This up-regulation was also observed in cells infected with other RNA and DNA viruses. Furthermore, we discovered that the type Ⅰ interferon signaling pathway positively regulated ZFAS1 expression. Functional assays revealed that silencing ZFAS1 significantly promoted IAV replication, while its overexpression significantly suppressed the virus replication. Additionally, LC-MS/MS analysis and Western blotting suggested that ZFAS1 encoded a 56-aa micropeptide, named ZFAS1-P56, which can also inhibit IAV replication. These results reveal that IAV-induced expression of ZFAS1 is regulated via the type Ⅰ interferon signaling pathway, and both ZFAS1 and ZFAS1-P56 suppress the IAV replication. This study unveils a new mechanism by which host establishes an innate immunity against the viral infection.