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bioRxiv · 10.64898/2026.01.02.697337

The targeted cytosolic degradation of class I histone deacetylases is essential for efficient alphaherpesvirus replication

Ming, S.·Du, M.-H.·Yang, J.-M.·Guo, Y.-D.·Pan, J.-J.·Lu, W.-F.·Wang, J.·Zeng, L.·Chu, B.-B.
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Abstract

Viral infection triggers a robust DNA damage response (DDR), reshaping the host chromatin landscape to facilitate viral replication. Here, we uncover a novel mechanism by which alphaherpesviruses exploit the DDR pathway. We demonstrated that herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) induced selective degradation of class I histone deacetylases (HDAC1/2), leading to histone hyperacetylation and subsequent DDR activation. Strikingly, viral infection promoted nuclear export of HDAC1/2, followed by MDM2-mediated K63-linked polyubiquitination and proteasomal degradation in the cytoplasm. Pharmacological inhibition of either DDR signaling or HDAC1/2 nuclear export significantly affected viral replication in vitro and in vivo. Our findings reveal a unique viral strategy to hijack host epigenetic regulation for efficient replication and identify potential therapeutic targets for alphaherpesvirus infections.

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Ming, S., Du, M.-H., Yang, J.-M., Guo, Y.-D., Pan, J.-J., Lu, W.-F., Wang, J., Zeng, L., Chu, B.-B.. 2026-01-02. The targeted cytosolic degradation of class I histone deacetylases is essential for efficient alphaherpesvirus replication. https://doi.org/10.64898/2026.01.02.697337

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