Abstract
The influenza A virus polymerase associates with a number of cellular transcription-related factors, including the RNA polymerase II (RNAP II). We previously described that the cellular protein hCLE/C14orf166 interacts with and stimulates influenza virus polymerase as well as RNAP II activities. Here we show that, despite the considerable cellular shut-off observed in infected cells, which includes RNAP II degradation, hCLE protein levels increase throughout infection in a virus replication-dependent manner. Human and avian influenza viruses of various subtypes increase hCLE levels, but other RNA or DNA viruses do not. hCLE colocalises and interacts with viral ribonucleoproteins (vRNP) in the nucleus, as well as in the cytoplasm late in infection. Furthermore, biochemical analysis of purified virus particles and immunoelectron microscopy of infected cells show hCLE in virions, in close association with viral vRNP. These findings indicate that hCLE, a cellular protein important for viral replication, is one of the very few examples of transcription factors that are incorporated into particles of an RNA-containing virus.
Highlights
Including RNAP II14, are reported to associate with the viral polymerase complex or its subunits
Other factors that interact with the viral polymerase are Ebp-1 15, which represses transcription of cell cycle genes regulated by E2F16; DDX517, a transcription co-activator that might have a role in cellular transcription initiation[18]; hStaufen[1], a protein involved in cellular mRNA transport that might participate in late events of influenza A virus (IAV) infection[19]; NXP2/ MORC317, a nuclear matrix protein involved in influenza virus transcription[20] and SFPQ/PSF factor[17], which increases the efficiency of viral mRNA polyadenylation[21]
These factors participate in cellular processes such as transcription, splicing and antiviral response, and should have effects on different stages of the IAV life cycle, such as genome transcription and replication, nuclear import and export of vRNP, translation, or virus morphogenesis and budding[46,47,48,49,50,51]
Summary
Including RNAP II14, are reported to associate with the viral polymerase complex or its subunits. Viral and cellular transcriptional machineries need to be coupled, RNAP II is degraded and cellular transcription is inhibited during IAV infection[27,28,29,30,31,32]. HCLE interacts with the unphosphorylated and phosphorylated forms of RNAP II Based on this interaction, cellular transcription is strongly dependent on hCLE, since a notable reduction in cellular mRNA synthesis is observed in hCLE-knockdown conditions[24,25]. Cellular transcription is strongly dependent on hCLE, since a notable reduction in cellular mRNA synthesis is observed in hCLE-knockdown conditions[24,25] Both hCLE-RNAP II interaction and hCLE control of mRNA synthesis make hCLE an appropriate target for degradation during infection, to prevent the antiviral response. In addition to its nuclear association, hCLE colocalises and interacts with vRNP in cytoplasm late in infection and is incorporated into virions in close association with packaged vRNP
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