Transcriptional factor ATF3 impairs KSHV lytic replication by suppressing the expression of viral bZIP protein K8

Kaposi’s Sarcoma-associated herpesvirus (KSHV) is a human gamma herpesvirus, establishing two different phases in its life cycle, latent infection and lytic replication. KSHV-encoded basic leucine zipper (bZIP) family of protein K8 (also called K-bZIP), an immediate-early protein, plays an indispensable role in KSHV lytic replication. Recombinant virus with K8 deletion exhibits an aberrant gene expression pattern and impairs virus production in KSHV lytic replication. However, the regulatory mechanisms of K8 itself expression have not been fully elucidated. In this study, we identified a host protein named activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors, interacting with K8 in nucleus. Meanwhile, we further determined that the bZIP domain of ATF3 is necessary for their interaction. Besides, we demonstrated that ATF3 works as an antiviral factor in KSHV lytic replication, inhibiting viral genes expression and impairing the production of progeny virions. Mechanistically, ATF3 associates with K8, leading to the repression of K8 promoter activity and thereby decreases the expression of K8 at both RNA and protein levels. Interestingly, we also verified that KSHV-encoded latency-associated nuclear antigen (LANA) could antagonize the antiviral activity of ATF3 by repressing ATF3 promoter activity to reduce its expression. Collectively, we identified that the transcription factor ATF3 as a novel binding partner of K8 and their interaction represses K8 promoter activity, leading to the reduction of K8 expression and consequently impairing KSHV lytic replication, which provide new insights into the development of novel antiviral strategies.