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bioRxiv · 10.64898/2026.10.05.756908

Promyelocytic leukemia (PML) suppresses hepatitis B virus cccDNA transcription through SUMOylation- and SMC5/6-dependent mechanisms

Wu, J.·Li, F.·Ahodantin, J.·Funaki, M.·Su, L.
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Abstract

Chronic hepatitis B virus (HBV) infection persists under current antiviral therapy because covalently closed circular DNA (cccDNA) remains in the infected hepatocytes as a durable transcriptional template. Although type I interferon (IFN-I) can reduce HBV cccDNA gene expression, the host effectors and mechanisms that restrict cccDNA remain incompletely defined. Using a minicircle-based HBV cccDNA expressing a Gaussia luciferase reporter gene (mcHBV-GLuc), we investigated how promyelocytic leukemia protein (PML) suppresses HBV cccDNA activity. Multiple PML isoforms reduced cccDNA-driven reporter activity and HBsAg production, and HBx-deficient ({Delta}X) mcHBV cccDNA was more susceptible than wild-type cccDNA to PML-mediated inhibition. Interestingly, efficient antiviral activity required the major PML SUMOylation sites. Disruption of SMC5/6 function attenuated PML-mediated repression of HBx-deficient cccDNA, associated with reduced PML SUMOylation and PML nuclear-body organization. These findings identify PML as a SUMO-dependent inhibitor of HBV cccDNA activity and reveal a context-dependent functional relationship between PML and SMC5/6 that is modulated by HBx.

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Wu, J., Li, F., Ahodantin, J., Funaki, M., Su, L.. 2026-10-09. Promyelocytic leukemia (PML) suppresses hepatitis B virus cccDNA transcription through SUMOylation- and SMC5/6-dependent mechanisms. https://doi.org/10.64898/2026.10.05.756908

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