Porcine Deltacoronavirus Infection Cleaves HDAC2 to Attenuate Its Antiviral Activity

Protein acetylation plays an important role during virus infection. Thus, it is not surprising that viruses always evolve elaborate mechanisms to regulate the functions of histone deacetylases (HDACs), the essential transcriptional and epigenetic regulators for deacetylation. Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets and has the potential to infect humans. In this study, we found that PDCoV infection inhibited cellular HDAC activity. By screening the expressions of different HDAC subfamilies after PDCoV infection, we unexpectedly found that HDAC2 was cleaved. Ectopic expression of HDAC2 significantly inhibited PDCoV replication, while the reverse effects could be observed after treatment with an HDAC2 inhibitor (CAY10683) or the knockdown of HDAC2 expression by specific siRNA. Furthermore, we demonstrated that PDCoV-encoded nonstructural protein 5 (nsp5), a 3C-like protease, was responsible for HDAC2 cleavage through its protease activity. Detailed analyses showed that PDCoV nsp5 cleaved HDAC2 at glutamine 261 (Q261), and the cleaved fragments (amino acids 1 to 261 and 262 to 488) lost the ability to inhibit PDCoV replication. Interestingly, the Q261 cleavage site is highly conserved in HDAC2 homologs from other mammalian species, and the nsp5s encoded by seven tested mammalian coronaviruses also cleaved HDAC2, suggesting that cleaving HDAC2 may be a common strategy used by different mammalian coronaviruses to antagonize the antiviral role of HDAC2. IMPORTANCE As an emerging porcine enteropathogenic coronavirus that possesses the potential to infect humans, porcine deltacoronavirus (PDCoV) is receiving increasing attention. In this work, we found that PDCoV infection downregulated cellular histone deacetylase (HDAC) activity. Of particular interest, the viral 3C-like protease, encoded by the PDCoV nonstructural protein 5 (nsp5), cleaved HDAC2, and this cleavage could be observed in the context of PDCoV infection. Furthermore, the cleavage of HDAC2 appears to be a common strategy among mammalian coronaviruses, including the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to antagonize the antiviral role of HDAC2. To our knowledge, PDCoV nsp5 is the first identified viral protein that can cleave cellular HDAC2. Results from our study provide new targets to develop drugs combating coronavirus infection.

 

Comments:

The provided text describes a study on the role of protein acetylation and histone deacetylases (HDACs) during porcine deltacoronavirus (PDCoV) infection. The study found that PDCoV infection inhibited cellular HDAC activity, and HDAC2, a specific subfamily of HDAC, was cleaved during infection. The researchers also discovered that the viral nonstructural protein 5 (nsp5), a 3C-like protease encoded by PDCoV, was responsible for the cleavage of HDAC2.

The study showed that ectopic expression of HDAC2 inhibited PDCoV replication, while inhibiting HDAC2 with an HDAC2 inhibitor or using specific siRNA to knockdown HDAC2 expression resulted in enhanced PDCoV replication. This suggests that HDAC2 plays a role in suppressing PDCoV infection. The researchers further identified the cleavage site of HDAC2 by PDCoV nsp5 at glutamine 261 (Q261), and the cleaved fragments of HDAC2 lost their ability to inhibit PDCoV replication.

Interestingly, the Q261 cleavage site was found to be highly conserved in HDAC2 homologs from other mammalian species, and nsp5 proteins encoded by seven tested mammalian coronaviruses also cleaved HDAC2. This suggests that cleaving HDAC2 may be a common strategy employed by different mammalian coronaviruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to counteract the antiviral role of HDAC2.

The study's findings shed light on the interactions between PDCoV and cellular HDACs, specifically HDAC2, and highlight the importance of protein acetylation during virus infection. The discovery of PDCoV nsp5 as the first viral protein identified to cleave cellular HDAC2 opens up new possibilities for developing drugs that can target this interaction and potentially combat coronavirus infections, including emerging ones like SARS-CoV-2.