The X protein of Borna disease virus regulates viral polymerase activity through interaction with the P protein

This study investigates how the X protein of Borna disease virus (BDV) negatively regulates viral polymerase activity. Using a minireplicon system in mammalian cells, the researchers demonstrated that X inhibits polymerase activity in a dose-dependent manner through direct interaction with the viral P protein, a cofactor of the polymerase complex. X mutants lacking the conserved leucine-rich N-terminal domain could not interact with P and failed to inhibit polymerase activity, while mutants retaining P-interaction capability maintained inhibitory function. A C-terminal P protein fragment containing only the X-interaction domain could act as a competitive decoy, neutralizing X's inhibitory effects. The study further showed that X causes cytoplasmic retention of P protein, which normally accumulates in the nucleus. The findings suggest X regulates BDV polymerase by sequestering P away from nuclear replication sites or disrupting P interactions with other viral components, potentially serving as a molecular buffer to fine-tune polymerase activity during different stages of viral infection.

Key findings

• The X protein inhibits BDV polymerase activity exclusively through interaction with the viral P protein cofactor
• X mutants unable to bind P protein fail to inhibit polymerase activity, regardless of other amino acid changes
• A truncated P protein fragment containing only the X-interaction domain can neutralize X inhibition, suggesting X acts as a P-sequestering factor
• X causes cytoplasmic retention of the P protein, potentially removing it from nuclear sites of viral replication
• X likely functions as a molecular buffer to fine-tune polymerase activity, particularly during different stages of infection