Brf1-Mediated RNA Polymerase III Activity Limits Murine Gammaherpesvirus Spread

RNA polymerase III (Pol III) activity, typically upregulated during herpesvirus infection, holds potential antiviral functions that have not been fully elucidated. In a study examining the role of the Pol III transcription factor Brf1 in murine gammaherpesvirus 68 (MHV68) infection, researchers depleted Brf1 to observe its impact on viral spread.

The results revealed that Brf1 depletion led to heightened MHV68 replication under low multiplicity of infection (MOI) conditions, accompanied by greater viral gene expression, protein accumulation, infectious virion production, and extracellular viral genome copies. This Brf1-specific effect was confirmed using an siRNA-resistant Brf1 construct.

However, under high MOI conditions, Brf1 depletion had only minimal effects, implying that Brf1-dependent antiviral activity is crucial during multistep viral spread. Transcriptomic analysis further showed that Brf1 deficiency accelerated the induction of interferon-responsive genes early in infection, followed by increased host transcript depletion at later stages, indicative of amplified host shutoff.

Crucially, genetic disruption of the RIG-I/MAVS signaling pathway did not negate Brf1's antiviral activity, demonstrating that this phenotype is independent of MAVS-dependent interferon signaling. Plaque assays corroborated these findings, indicating that Brf1-deficient cells supported larger plaques and increased plaque numbers, suggesting enhanced viral spread and/or entry.

In summary, these findings underscore an unexpected role for Brf1-dependent Pol III activity in controlling gammaherpesvirus spread, highlighting the potential of virus-induced Pol III activation as a mechanism contributing to host antiviral defense.