tetano
Editor, Senior Moderator
J Virol. 2014 Jul 16. pii: JVI.00727-14. [Epub ahead of print]
Histone deacetylase 6 inhibits influenza A virus release by downregulating the trafficking of viral components to the plasma membrane via its substrate acetylated microtubules.
Husain M1, Cheung CY2.
Author information
Abstract
Mammalian cells produce many proteins such as IFITM3, ISG15, MxA, and viperin that inhibit influenza A virus (IAV) infection. Here we show that a new class of host protein, histone deacetylase 6 (HDAC6) inhibits IAV infection. We found that the HDAC6-overexpressing cells release about 3-fold less IAV progeny, whereas the HDAC6-depleted cells release about 6-fold more IAV progeny. The deacetylase activity of HDAC6 played a role in its anti-IAV function as tubacin, a specific small-molecule inhibitor of HDAC6, increased the release of IAV progeny in a dose-dependent manner. Further, as visualized by the electron microscopy, tubacin-treated cells showed an increase in IAV budding at the plasma membrane, the site of IAV assembly. Tubacin is a domain-specific inhibitor and binds to one of the two HDAC6 catalytic domains possessing the tubulin deacetylase activity. This indicated the potential involvement of acetylated microtubules in the trafficking of viral components to the plasma membrane. Indeed, as quantified by flow cytometry, there was about 2.0 to 2.5-fold increase and about 2-fold decrease in the amount of viral envelope protein hemagglutinin present on the plasma membrane of tubacin-treated, HDAC6-depleted, and HDAC6-overexpressing cells, respectively. In addition, the viral ribonucleoprotein complex was co-localized with acetylated microtubule filaments and viral nucleoprotein co-immunoprecipitated with acetylated tubulin. Together, our findings indicate that HDAC6 is an anti-IAV host factor and exerts its anti-IAV function by negatively regulating the trafficking of viral components to the host cell plasma membrane via its substrate acetylated microtubules.
IMPORTANCE:
Host cells produce many proteins that have the natural ability to restrict the influenza virus infection. Herein, we discovered that another host protein, histone deacetylase 6 (HDAC6) inhibits the influenza virus infection. We demonstrate that HDAC6 exerts its anti-influenza function by negatively regulating the trafficking of viral components to the site of influenza virus assembly via its substrate acetylated microtubules. HDAC6 is a multi-substrate enzyme and regulates multiple cellular pathways including the ones leading to various cancers, neurodegenerative diseases, and inflammatory disorders. Therefore, several drugs targeting HDAC6 are under clinical development for the treatment of wide range of diseases. Influenza virus continues to be a major global public health problem due to regular emergence of drug-resistant and novel influenza strains in humans. As an alternative antiviral strategy, HDAC6 modulators could be employed to stimulate the anti-influenza potential of endogenous HDAC6 to inhibit influenza virus infection.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25031336
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25031336
Histone deacetylase 6 inhibits influenza A virus release by downregulating the trafficking of viral components to the plasma membrane via its substrate acetylated microtubules.
Husain M1, Cheung CY2.
Author information
Abstract
Mammalian cells produce many proteins such as IFITM3, ISG15, MxA, and viperin that inhibit influenza A virus (IAV) infection. Here we show that a new class of host protein, histone deacetylase 6 (HDAC6) inhibits IAV infection. We found that the HDAC6-overexpressing cells release about 3-fold less IAV progeny, whereas the HDAC6-depleted cells release about 6-fold more IAV progeny. The deacetylase activity of HDAC6 played a role in its anti-IAV function as tubacin, a specific small-molecule inhibitor of HDAC6, increased the release of IAV progeny in a dose-dependent manner. Further, as visualized by the electron microscopy, tubacin-treated cells showed an increase in IAV budding at the plasma membrane, the site of IAV assembly. Tubacin is a domain-specific inhibitor and binds to one of the two HDAC6 catalytic domains possessing the tubulin deacetylase activity. This indicated the potential involvement of acetylated microtubules in the trafficking of viral components to the plasma membrane. Indeed, as quantified by flow cytometry, there was about 2.0 to 2.5-fold increase and about 2-fold decrease in the amount of viral envelope protein hemagglutinin present on the plasma membrane of tubacin-treated, HDAC6-depleted, and HDAC6-overexpressing cells, respectively. In addition, the viral ribonucleoprotein complex was co-localized with acetylated microtubule filaments and viral nucleoprotein co-immunoprecipitated with acetylated tubulin. Together, our findings indicate that HDAC6 is an anti-IAV host factor and exerts its anti-IAV function by negatively regulating the trafficking of viral components to the host cell plasma membrane via its substrate acetylated microtubules.
IMPORTANCE:
Host cells produce many proteins that have the natural ability to restrict the influenza virus infection. Herein, we discovered that another host protein, histone deacetylase 6 (HDAC6) inhibits the influenza virus infection. We demonstrate that HDAC6 exerts its anti-influenza function by negatively regulating the trafficking of viral components to the site of influenza virus assembly via its substrate acetylated microtubules. HDAC6 is a multi-substrate enzyme and regulates multiple cellular pathways including the ones leading to various cancers, neurodegenerative diseases, and inflammatory disorders. Therefore, several drugs targeting HDAC6 are under clinical development for the treatment of wide range of diseases. Influenza virus continues to be a major global public health problem due to regular emergence of drug-resistant and novel influenza strains in humans. As an alternative antiviral strategy, HDAC6 modulators could be employed to stimulate the anti-influenza potential of endogenous HDAC6 to inhibit influenza virus infection.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25031336
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25031336