Influenza A virus-induced host caspase and viral PA-X antagonize the antiviral host factor, histone deacetylase 4.
Influenza A virus (IAV) effectively manipulates host machinery to replicate. There is a growing evidence that an optimal acetylation environment in the host cell is favorable to IAV proliferation and vice versa. The histone deacetylases (HDACs), a family of 18 host enzymes classified into four classes, are central to negatively regulating the acetylation level, hence the HDACs would not be favorable to IAV. Indeed, by using the RNAi and overexpression strategies, we found that human HDAC4, a class II member, possesses anti-IAV properties and is a component of host innate antiviral response. We discovered that IAV multiplication was augmented in HDAC4-depleted cells and abated in HDAC4-supplemented cells. Likewise, the expression of IFITM3, ISG15, and viperin, some of the critical markers of host anti-IAV response was abated in HDAC4-depleted cells and augmented in HDAC4-supplemented cells. In turn, IAV strongly antagonizes the HDAC4, by down-regulating its expression both at the mRNA level via viral RNA endonuclease PA-X and at the polypeptide level by inducing its cleavage via host caspase 3 in infected cells. Such HDAC4 polypeptide cleavage resulted in a ∼30 kDa fragment that is also observed in some heterologous systems and may have a significant role in IAV replication.
['Galvin|Henry D|HD|', 'Husain|Matloob|M|0000-0002-4413-6220']
D000072283:A549 Cells D053148:Caspase 3 D016207:Cytokines D015536:Down-Regulation D006655:Histone Deacetylases D006801:Humans D007113:Immunity, Innate D009980:Influenza A virus D008565:Membrane Proteins D044925:Oxidoreductases Acting on CH-CH Group Donors D010766:Phosphorylation D011506:Proteins D034622:RNA Interference D034741:RNA, Small Interfering D016601:RNA-Binding Proteins D012097:Repressor Proteins D050794:STAT1 Transcription Factor D014452:Ubiquitins D017361:Viral Nonstructural Proteins
PA-X IFITM3 ISG15 viperin PA histone deacetylase 4 (HDAC4) host defense host-pathogen interaction influenza virus innate immunity signal transducers and activators of transcription 1 (STAT1)