Barrier-to-autointegration Factor 1 (BAF) Promotes Gammaherpesvirus Reactivation from Latency

Gammaherpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are DNA viruses that are globally associated with human cancers and establish lifelong latency in the human population. Detection of gammaherpesviral infection by the cGAS-STING innate immune DNA-sensing pathway is critical for suppressing viral reactivation from latency, a process that promotes viral pathogenesis and transmission. We report that Barrier-to-autointegration factor 1 (BAF)-mediated suppression of the cGAS-STING signaling pathway is necessary for reactivation of KSHV and EBV. We demonstrate a novel role for BAF in destabilizing cGAS expression and show that BAF expression in latently infected, reactivating, or uninfected cells leads to suppression of type I interferon-mediated antiviral responses and inhibition of viral replication. Furthermore, BAF overexpression resulted in decreased cGAS expression at the protein level. These results establish BAF as a key regulator of the lifecycle of gammaherpesviruses and a potential target for treating viral infections and malignancies. Comparative gene expression profiling analysis of RNA-seq data for iSLK.219 cells treated with non-targeting control (NTC) siRNA or BANF1-targeting (BAF) siRNA. Cells in each siRNA treatment group was harvested before and after 48 hours of doxycycline treatment to reactivate KSHV lytic gene expression. Duplicate biological replicates were collected for each condition/timepoint combination.