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

Abstract

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 Virus Host Restriction Factors: The ISGs and Non-ISGs

“…Influenza virus overcomes the antiviral function of HDACs by downregulating their expression at both mRNA and protein levels [ 255 , 256 , 257 , 260 , 261 , 269 , 270 ], as well as their enzymatic activity [ 255 , 258 , 271 ]. Specifically, influenza virus downregulates the expression of HDAC4 and HDAC6 mRNA via PA [ 260 , 270 ] and HDAC8 mRNA via miR-21-3p [ 261 ]. Further, influenza virus exploits the host proteasome and caspases to promote the degradation of HDAC1 and HDAC2 [ 255 , 256 ] and HDAC4 and HDAC6 [ 260 , 270 ], respectively.…”

“…Specifically, influenza virus downregulates the expression of HDAC4 and HDAC6 mRNA via PA [ 260 , 270 ] and HDAC8 mRNA via miR-21-3p [ 261 ]. Further, influenza virus exploits the host proteasome and caspases to promote the degradation of HDAC1 and HDAC2 [ 255 , 256 ] and HDAC4 and HDAC6 [ 260 , 270 ], respectively.…”

Influenza A Virus and Acetylation: The Picture Is Becoming Clearer

“…Hence, IAV must antagonize the HDACs to maintain optimal acetylation levels of those proteins and successfully replicate. IAV has been discovered to antagonize the HDACs by downregulating both their expression [ 53 , 54 , 55 , 56 , 64 , 82 , 83 ] and activity [ 50 , 55 , 57 ] in infected cells. To downregulate the expression of HDACs at the mRNA level, IAV employs both viral and host components.…”

“…To downregulate the expression of HDACs at the mRNA level, IAV employs both viral and host components. For example, IAV employs its proteins, PA-X and PA, to downregulate the mRNA levels of HDAC4 [ 56 ] and HDAC6 [ 82 ], respectively. Notably, both PA-X and PA possess the endonuclease function, and particularly, PA-X is instrumental in host shutoff activity [ 26 ].…”

“…To downregulate the expression of HDACs at the protein level, IAV employs host proteasome- and caspase-mediated protein degradation mechanisms, which seem to be tailored for the HDACs from a particular class. The class I HDACs, HDAC1 and HDAC2, are degraded in infected cells by proteasome pathway [ 54 , 55 ], whereas, the class II HDACs, HDAC4 and HDAC6, are degraded by caspases [ 56 , 82 ].…”