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Toosendanin From Melia Fructus Suppresses Influenza A Virus Infection by Altering Nuclear Localization of Viral Polymerase PA Protein.

ABSTRACT: Toosendanin (TSN) is a major bioactive component of Melia Fructus (MF) with anti-inflammatory, anti-botulinum, anti-microbial, and analgesic efficacy. Our previous study demonstrated that MF has anti-influenza A virus activity; however, the contribution of TSN is still unclear. In this study, we found that TSN suppressed influenza A virus infection when administered before or concurrent with the virus, but not after infection. TSN pretreatment inhibited viral hemagglutinin (HA), nucleoprotein (NP), polymerase acidic (PA) protein, and matrix protein 2 (M2) mRNA synthesis as well as NP, PA, M2, and nonstructural protein 1 (NS1) expression but had no effect on HA or neuraminidase (NA) activity. In addition, TSN induced cytoplasmic location of PA protein disrupting nuclear translocation. Docking simulation suggested that the binding affinity of TSN to PA protein may be stronger than that of a known PA protein inhibitor. Pretreatment with TSN also suppressed the infection-induced phospho-AKT expression but not the host immune response. Oral pretreatment with TSN enhanced the survival of infected mice. These results suggest that TSN inhibits influenza A virus infection at an early stage by altering PA protein nuclear localization. Thus, TSN may be a promising candidate for anti-influenza agent targeting the PA protein of the influenza A virus RNA polymerase complex.

SUBMITTER: Jin YH

PROVIDER: S-EPMC6757512 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Toosendanin From Melia Fructus Suppresses Influenza A Virus Infection by Altering Nuclear Localization of Viral Polymerase PA Protein.

Jin Young-Hee YH Kwon Sunoh S Choi Jang-Gi JG Cho Won-Kyung WK Lee Bonggi B Ma Jin Yeul JY

Frontiers in pharmacology 20190912

Toosendanin (TSN) is a major bioactive component of Melia Fructus (MF) with anti-inflammatory, anti-botulinum, anti-microbial, and analgesic efficacy. Our previous study demonstrated that MF has anti-influenza A virus activity; however, the contribution of TSN is still unclear. In this study, we found that TSN suppressed influenza A virus infection when administered before or concurrent with the virus, but not after infection. TSN pretreatment inhibited viral hemagglutinin (HA), nucleoprotein (N ...[more]

PMID: 31607903

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Project description:Meliae Fructus (MF) is the dried ripe fruit of Melia toosendan Siebold et Zuccarini, Meliaceae family. MF is widely used in traditional medicine to treat inflammation and helminthic infection and has anti-bacterial, anti-oxidant, anti-cancer, anti-inflammatory, and analgesic activities. However, potential anti-influenza properties of MF have yet to be investigated. We determined whether an ethanolic extract of MF (EMF) has anti-viral activity via an EMF pre-, co-, and post-treatment assay, using the Influenza A/PR/8/34 and H3N2 virus on Madin-Darby canine kidney (MDCK) cells. The EMF had anti-influenza virus activity in pre- and co-treated cells in a dose-dependent manner, but not in post-treated cell. EMF inhibited the activity of hemagglutinin (HA) and neuraminidase (NA) of influenza virus. EMF inhibited viral HA, nucleoprotein (NP), matrix protein 2 (M2), non-structural protein 1 (NS1), polymerase acidic protein (PA), polymerase basic protein 1 (PB1), and polymerase basic protein 2 (PB2) mRNA synthesis at 5 h post infection (hpi), however, the levels of PA, PB1, and PB2 mRNA were increased in pre- and co-EMF treated cells compared with control virus-infected and EMF post-treated cells at 18 hpi. The level of M2 protein expression was also decreased upon pre- and co-treatment with EMF. The PA protein was accumulated and localized in not only the nucleus but also the cytoplasm of virus-infected MDCK cells at 18 hpi. Pre-EMF treatment inhibited the expression of pAKT, which is induced by influenza virus infection, at the stage of virus entry. We also found that treatment of EMF up-regulated the antiviral protein Mx1, which may play a partial role in inhibiting influenza virus infection in pre- and co-EMF treated MDCK cells. In summary, these results strongly suggested that an ethanolic extract of Meliae Fructus inhibited influenza A virus infection by affecting viral entry, PA proteins of the RNA polymerase complex, and Mx1 induction and may be a potential and novel anti-influenza agent.

Project description:The life cycle of influenza A virus (IAV) is modulated by various cellular host factors. Although previous studies indicated that IAV infection is controlled by HDAC6, the deacetylase involved in the regulation of PA remained unknown. Here, we demonstrate that HDAC6 acts as a negative regulator of IAV infection by destabilizing PA. HDAC6 binds to and deacetylates PA, thereby promoting the proteasomal degradation of PA. Based on mass spectrometric analysis, Lys(664) of PA can be deacetylated by HDAC6, and the residue is crucial for PA protein stability. The deacetylase activity of HDAC6 is required for anti-IAV activity, because IAV infection was enhanced due to elevated IAV RNA polymerase activity upon HDAC6 depletion and an HDAC6 deacetylase dead mutant (HDAC6-DM; H216A, H611A). Finally, we also demonstrate that overexpression of HDAC6 suppresses IAV RNA polymerase activity, but HDAC6-DM does not. Taken together, our findings provide initial evidence that HDAC6 plays a negative role in IAV RNA polymerase activity by deacetylating PA and thus restricts IAV RNA transcription and replication.IMPORTANCE Influenza A virus (IAV) continues to threaten global public health due to drug resistance and the emergence of frequently mutated strains. Thus, it is critical to find new strategies to control IAV infection. Here, we discover one host protein, HDAC6, that can inhibit viral RNA polymerase activity by deacetylating PA and thus suppresses virus RNA replication and transcription. Previously, it was reported that IAV can utilize the HDAC6-dependent aggresome formation mechanism to promote virus uncoating, but HDAC6-mediated deacetylation of α-tubulin inhibits viral protein trafficking at late stages of the virus life cycle. These findings together will contribute to a better understanding of the role of HDAC6 in regulating IAV infection. Understanding the molecular mechanisms of HDAC6 at various periods of viral infection may illuminate novel strategies for developing antiviral drugs.

Dataset Information

Toosendanin From Melia Fructus Suppresses Influenza A Virus Infection by Altering Nuclear Localization of Viral Polymerase PA Protein.

Publications

Toosendanin From Melia Fructus Suppresses Influenza A Virus Infection by Altering Nuclear Localization of Viral Polymerase PA Protein.

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