tetano
Editor, Senior Moderator
J Virol. 2018 Dec 5. pii: JVI.01896-18. doi: 10.1128/JVI.01896-18. [Epub ahead of print]
[h=1]HDAC6 restricts influenza A virus by deacetylation of the RNA polymerase PA subunit.[/h] Chen H[SUP]1,[/SUP][SUP]2[/SUP], Qian Y[SUP]1,[/SUP][SUP]2[/SUP], Chen X[SUP]1,[/SUP][SUP]2[/SUP], Ruan Z[SUP]1,[/SUP][SUP]2[/SUP], Ye Y[SUP]1,[/SUP][SUP]2[/SUP], Chen H[SUP]3[/SUP], Babiuk LA[SUP]4[/SUP], Jung YS[SUP]5,[/SUP][SUP]2[/SUP], Dai J[SUP]1,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The life cycle of the influenza A virus (IAV) is modulated by various cellular host factors. Although earlier studies indicated that IAV infection is controlled by HDAC6, the deacetylase involved in the regulation of PA remained unknown. Here, we demonstrated that HDAC6 acts as a negative regulator of IAV infection through destabilizing PA. HDAC6 binds to and deacetylates PA, thereby promoting the proteasomal degradation of PA. Through mass spectrometric analysis, Lys(664) of PA can be deacetylated by HDAC6 and this 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 HDAC6 deacetylase dead mutant (HDAC6-DM, H216A;H611A). Finally, we also demonstrated that overexpression of HDAC6 suppresses the IAV RNA polymerase activity, but HDAC6-DM does not. Taken together, our findings provide the initial evidence that HDAC6 plays a negative role in IAV RNA polymerase activity via deacetylating PA and thus restricts IAV RNA transcription and replication.IMPORTANCE Influenza A virus (IAV) continues to threat global public health due to drug resistance and the emergency of frequently mutated strains of IAV. Thus, it is critical to find new strategies to control IAV infection. Here we discovered one host protein, HDAC6, which can inhibit viral RNA polymerase activity through 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 ofα-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 in various periods of viral infection may illuminate novel strategies for developing antiviral drugs.
PMID: 30518648 DOI: 10.1128/JVI.01896-18
[h=1]HDAC6 restricts influenza A virus by deacetylation of the RNA polymerase PA subunit.[/h] Chen H[SUP]1,[/SUP][SUP]2[/SUP], Qian Y[SUP]1,[/SUP][SUP]2[/SUP], Chen X[SUP]1,[/SUP][SUP]2[/SUP], Ruan Z[SUP]1,[/SUP][SUP]2[/SUP], Ye Y[SUP]1,[/SUP][SUP]2[/SUP], Chen H[SUP]3[/SUP], Babiuk LA[SUP]4[/SUP], Jung YS[SUP]5,[/SUP][SUP]2[/SUP], Dai J[SUP]1,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The life cycle of the influenza A virus (IAV) is modulated by various cellular host factors. Although earlier studies indicated that IAV infection is controlled by HDAC6, the deacetylase involved in the regulation of PA remained unknown. Here, we demonstrated that HDAC6 acts as a negative regulator of IAV infection through destabilizing PA. HDAC6 binds to and deacetylates PA, thereby promoting the proteasomal degradation of PA. Through mass spectrometric analysis, Lys(664) of PA can be deacetylated by HDAC6 and this 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 HDAC6 deacetylase dead mutant (HDAC6-DM, H216A;H611A). Finally, we also demonstrated that overexpression of HDAC6 suppresses the IAV RNA polymerase activity, but HDAC6-DM does not. Taken together, our findings provide the initial evidence that HDAC6 plays a negative role in IAV RNA polymerase activity via deacetylating PA and thus restricts IAV RNA transcription and replication.IMPORTANCE Influenza A virus (IAV) continues to threat global public health due to drug resistance and the emergency of frequently mutated strains of IAV. Thus, it is critical to find new strategies to control IAV infection. Here we discovered one host protein, HDAC6, which can inhibit viral RNA polymerase activity through 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 ofα-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 in various periods of viral infection may illuminate novel strategies for developing antiviral drugs.
PMID: 30518648 DOI: 10.1128/JVI.01896-18