Unfolding HBx for an epigenetic switch of HBV cccDNA minichromosome

The Hepatitis B virus (HBV) life cycle involves converting its relaxed circular DNA into covalently closed circular (ccc) DNA, which is silenced by heterochromatin through host restriction mechanisms. The HBV X protein (HBx) overcomes this repression to sustain infection. Recent studies show that the N-terminal motif of HBx recruits Spindlin1, a histone methylation reader, to unlock its repressive function and promote transcription. AlphaFold structural predictions indicate that HBx unfolds to expose motifs for Spindlin1, damaged DNA binding protein 1 (DDB1), and the B cell lymphoma-2 (Bcl-2) protein recruitment, switching from a repressive to an active state. HBx thus exhibits dual functional states: in the folded state, it recruits co-repressors to maintain heterochromatin; in the unfolded state, it recruits Spindlin1 along with DDB1 and Bcl-2 to form euchromatin. This dual-state conformational switch-driven epigenetic reprogramming mechanism can inform new therapeutic strategies for HBV-related liver diseases.