PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

Abstract

Influenza A virus (IAV) utilizes multiple strategies to confront or evade host type I interferon (IFN)-mediated antiviral responses in order to enhance its own propagation within the host. One such strategy is to induce the degradation of type I IFN receptor 1 (IFNAR1) by utilizing viral hemagglutinin (HA). However, the molecular mechanism behind this process is poorly understood. Here, we report that a cellular protein, poly(ADP-ribose) polymerase 1 (PARP1), plays a critical role in mediating IAV HA-induced degradation of IFNAR1. We identified PARP1 as an interacting partner for IAV HA through mass spectrometry analysis. This interaction was confirmed by coimmunoprecipitation analyses. Furthermore, confocal fluorescence microscopy showed altered localization of endogenous PARP1 upon transient IAV HA expression or during IAV infection. Knockdown or inhibition of PARP1 rescued IFNAR1 levels upon IAV infection or HA expression, exemplifying the importance of PARP1 for IAV-induced reduction of IFNAR1. Notably, PARP1 was crucial for the robust replication of IAV, which was associated with regulation of the type I IFN receptor signaling pathway. These results indicate that PARP1 promotes IAV replication by controlling viral HA-induced degradation of host type I IFN receptor. Altogether, these findings provide novel insight into interactions between influenza virus and the host innate immune response and reveal a new function for PARP1 during influenza virus infection. IMPORTANCE Influenza A virus (IAV) infections cause seasonal and pandemic influenza outbreaks, which pose a devastating global health concern. Despite the availability of antivirals against influenza, new IAV strains continue to persist by overcoming the therapeutics. Therefore, much emphasis in the field is placed on identifying new therapeutic targets that can more effectively control influenza. IAV utilizes several tactics to evade host innate immunity, which include the evasion of antiviral type I interferon (IFN) responses. Degradation of type I IFN receptor (IFNAR) is one known method of subversion, but the molecular mechanism for IFNAR downregulation during IAV infection remains unclear. Here, we have found that a host protein, poly(ADP-ribose) polymerase 1 (PARP1), facilitates IFNAR degradation and accelerates IAV replication. The findings reveal a novel cellular target for the potential development of antivirals against influenza, as well as expand our base of knowledge regarding interactions between influenza and the host innate immunity.

A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

“…Several previous studies have demonstrated that PARP1 is critical for viral replication [35,42,43]. For example, PARP1 has been reported to interact with hemagglutinin (HA) of influenza A virus (IAV) and promote its replication by triggering the degradation of host type I IFN receptor [44]. In addition, the ADP-ribosylation of adenoviral core proteins displays an antiviral defense mechanism [34].…”

Differential immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung and intestinal cells: Implications for treatment with IFN-β and IFN inducer

“…Viruses can employ a variety of mechanisms to suppress the host innate immune system, [33][34][35] thus evading from crucial antiviral responses, like the IFN signaling pathways, to facilitate virus propagation and dissemination. Here, our study demonstrated that SARS-CoV-2 infection induced attenuated pro-inflammatory cytokines/chemokines and IFN responses in both Calu3 and Caco2 cells, despite robust virus infection and propagation.…”

Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

“…For instance, HA protein was shown to trigger ubiquitination of IFNAR to attenuate the type I IFN signaling pathway [162]. The follow-up work showed that poly (ADP-ribose) polymerase 1 (PARP1) functions as an interacting partner of HA protein to mediate the HA-induced IFNAR degradation [163]. NS1 is the most important IFNs antagonist protein via mechanisms including inhibition of the TRIM25-mediated RIG-I ubiquitination, suppression of protein kinase R (PKR), phosphorylation of IκB kinases (IKK) α and β in the NF-κB pathway, interruption of the phosphorylation of STAT1, STAT2, and STAT3 [39,115], and degradation of OTUB1 [138].…”