Anti‐microbial host factor HDAC6 is antagonised by the influenza A virus through host caspases and viral PA

• Published in: The FEBS journal 2023-05, Vol.290 (10), p.2744-2759
• Main Authors: Hussain, Mazhar, Ahmed, Farjana, Henzeler, Bennett, Husain, Matloob
• Format: Article
• Language: English
• Subjects: Addition polymerization; Antagonism; Apoptosis; caspase; Caspase-3; Caspase-6; Caspases - metabolism; Depletion; DNA-directed RNA polymerase; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Fragments; Gene expression; Histone deacetylase; histone deacetylase 6; Histone Deacetylase 6 - genetics; Histone Deacetylase 6 - metabolism; Host-Pathogen Interactions; Humans; Infections; Influenza; Influenza A; influenza A virus; Influenza A virus - metabolism; Influenza, Human - genetics; lysosome; Microorganisms; Nucleotidyltransferases - metabolism; Peptides - metabolism; Polypeptides; Proteins; RNA polymerase; Substrates; Viral Proteins - genetics; Viral Proteins - metabolism; viral RNA polymerase subunit PA; Virus Replication - genetics; Viruses
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16703

Histone deacetylase 6 (HDAC6), through the repertoire of its substrate proteins, plays a critical role in human physiology, and an aberrant function of HDAC6 contributes to various pathophysiological conditions. HDAC6 is also known to be an anti‐microbial host factor and has been implicated in restricting or clearing the infection of various human viral and bacterial pathogens. However, the state and the mechanisms of its antagonism in infected cells are not understood. Here, we demonstrate that influenza A virus (IAV) antagonises HDAC6 by recruiting both viral and host components. We found that HDAC6 mRNA expression, and consequently, the HDAC6 polypeptide expression is downregulated in human lung epithelial cells during early stage of IAV infection but can be rescued by depleting the expression of viral polymerase acidic (PA) protein, a subunit of IAV RNA polymerase. In addition, during later stage of the infection, the HDAC6 polypeptide undergoes caspase‐mediated cleavage at two sites, generating two cleaved fragments. Both these fragments disappeared when the expression of caspase 3 was depleted in infected cells, whereas only second fragment disappeared when the expression of caspase 6 was depleted. But both fragments disappeared and the level of full‐length HDAC6 polypeptide was rescued when the expression of PA was depleted in infected cells. Collectively, these data indicated that IAV antagonises the HDAC6 by decreasing its expression level in infected cells, both at mRNA and polypeptide level via PA gene, which has been implicated in auxiliary functions like degradation of host mRNA and induction of apoptosis. Influenza A virus antagonises the anti‐microbial host factor, HDAC6 at both mRNA and polypeptide level via viral PA. During the early stage of infection, PA degrades HDAC6 mRNA, potentially through its endonuclease activity. During the later stage of infection, PA activates host caspase 3, which then cleaves HDAC6 polypeptide at position 1088. In parallel, caspase 3 activates host caspase 6 which cleaves HDAC6 polypeptide at a site between position 650 and 950.