Abstract
Many cellular genes and networks induced in human lung epithelial cells infected with the influenza virus remain uncharacterized. Here, we find that p21 levels are elevated in response to influenza A virus (IAV) infection, which is independent of p53. Silencing, pharmacological inhibition or deletion of p21 promotes virus replication in vitro and in vivo, indicating that p21 is an influenza restriction factor. Mechanistically, p21 binds to the C-terminus of IAV polymerase subunit PA and competes with PB1 to limit IAV polymerase activity. Besides, p21 promotes IRF3 activation by blocking K48-linked ubiquitination degradation of HO-1 to enhance type I interferons expression. Furthermore, a synthetic p21 peptide (amino acids 36 to 43) significantly inhibits IAV replication in vitro and in vivo. Collectively, our findings reveal that p21 restricts IAV by perturbing the viral polymerase complex and activating the host innate immune response, which may aid the design of desperately needed new antiviral therapeutics.
Highlights
Influenza A virus (IAV) is one of the most common respiratory tract pathogens, causing at least 500,000 deaths each year worldwide [1,2,3,4]
We demonstrate that p21 directly binds to the viral polymerase acidic protein and limits IAV polymerase activity through disrupting the formation of the ribonucleoprotein complex
On the basis of a threshold fold change of Z > 2.0 and a P-value < 1 × 10−90, we further conducted an small interfering RNA (siRNA) screen in A549 cells using a library against the top 60 upregulated genes that had not been previously defined; viral RNA copies were quantified by qRT-PCR as the endpoint
Summary
Influenza A virus (IAV) is one of the most common respiratory tract pathogens, causing at least 500,000 deaths each year worldwide [1,2,3,4]. The influenza pandemic of 1918 killed more than 50 million people worldwide [5]. H1N1 and H3N2 are the dominant seasonal IAVs responsible for yearly epidemics that affect 5%–15% of the population, in which they cause upper respiratory tract infections [6]. Over the past few decades, vaccines and antiviral drugs have achieved great success in the control and treatment of IAV infections; seasonal IAV still persists [8,9,10]. New antiviral strategies, including different viral targets, cellular targets or immune-modulating drugs, are urgently needed
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