Histone Deacetylase 2 Is a Component of Influenza A Virus-Induced Host Antiviral Response

Abstract

Host cells produce variety of antiviral factors that create an antiviral state and target various stages of influenza A virus (IAV) life cycle to inhibit infection. However, IAV has evolved various strategies to antagonize those antiviral factors. Recently, we reported that a member of class I host histone deacetylases (HDACs), HDAC1 possesses an anti-IAV function. Herein, we provide evidence that HDAC2, another class I member and closely related to HDAC1 in structure and function, also possesses anti-IAV properties. In turn, IAV, like HDAC1, dysregulates HDAC2, mainly at the polypeptide level through proteasomal degradation to potentially minimize its antiviral effect. We found that IAV downregulated the HDAC2 polypeptide level in A549 cells in an H1N1 strain-independent manner by up to 47%, which was recovered to almost 100% level in the presence of proteasome-inhibitor MG132. A further knockdown in HDAC2 expression by up to 90% via RNA interference augmented the growth kinetics of IAV in A549 cells by more than four-fold after 24 h of infection. Furthermore, the knockdown of HDAC2 expression decreased the IAV-induced phosphorylation of the transcription factor, Signal Transducer and Activator of Transcription I (STAT1) and the expression of interferon-stimulated gene, viperin in infected cells by 41 and 53%, respectively. The role of HDAC2 in viperin expression was analogous to that of HDAC1, but it was not in the phosphorylation of STAT1. This indicated that, like HDAC1, HDAC2 is a component of IAV-induced host innate antiviral response and performs both redundant and non-redundant functions vis-a-vis HDAC1; however, IAV dysregulates them both in a redundant manner.

The Class IV human deacetylase, HDAC11, exhibits anti‐influenza A virus properties via its involvement in host innate antiviral response

“…However, only Class I and Class II HDACs have been shown to be implicated in this phenomenon (Carlomagno et al, ; Krämer & Heinzel, ; Yan et al, ). In agreement with this, we earlier showed that IAV‐induced phosphorylation of STAT1 is downregulated in HDAC inhibitor‐treated (Nagesh & Husain, ) or HDAC2‐depleted cells (Nagesh et al, ). Likewise, as shown herein, the IAV‐induced (as well as IFNα‐induced) phosphorylation of STAT1 is also downregulated in HDAC11‐depleted cells.…”

“…This indicates that HDAC11 siRNA does contribute to further reducing the HDAC11 mRNA level during the course of infection and, consequently, to IAV proliferation. The extent of increase in virus release from HDAC11‐depleted cells was larger than about 3.0‐, 4.0‐, and 6.0‐fold increase from HDAC 1‐, 2‐, and 6‐depleted cells, respectively, we observed earlier (Husain & Cheung, ; Nagesh et al, ; Nagesh & Husain, ). One of the possible explanations for this could be that, compared with the Classes I and II HDACs, HDAC11 is evolutionarily the least evolved HDAC and has retained the original structure as well as function assigned to its common ancestral gene(s) by nature.…”

“…The data presented above demonstrating the noticeably significant proliferation of IAV in HDAC11‐depleted cells and a profound downregulation of HDAC11 transcript level in infected cells—a sign of viral antagonism of HDAC11—indicated that, like HDAC 1 and 2 (Nagesh et al, ; Nagesh & Husain, ), HDAC11 is part of the host defences. Therefore, we next investigated the role of HDAC11 in IAV‐mediated induction of host IFN response.…”

“…We have identified and characterised a role of multiple human histone deacetylases (HDACs) in IAV infection (Husain & Cheung, ; Nagesh & Husain, ; Nagesh, Hussain, Galvin, & Husain, ). The HDACs are a family of enzymes that were originally described to catalyse the deacetylation of acetylated histones (Seto & Yoshida, ).…”

“…Finally, Class IV possesses a lone member, HDAC11. We have found that members of both the Class I (HDAC 1 and 2) and Class II (HDAC6) possess anti‐IAV properties (Husain & Cheung, ; Nagesh et al, ; Nagesh & Husain, ). Furthermore, all Class III HDACs (SIRT) have been found to exhibit anti‐IAV properties too (Koyuncu et al, ).…”