KSHV miRNAs target STING to evade innate immunity and facilitate KSHV lytic reactivation from latency.

Kaposi sarcoma-associated herpesvirus (KSHV) employs various strategies to evade host immune surveillance and maintain lifelong latency. The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) DNA sensing pathway is a key innate immunity pathway that detects viral DNA and restricts KSHV lytic replication upon reactivation from latency. Here, we identify three KSHV microRNAs (miRNAs), miR-K12-6-3p, miR-K12-7-3p, and miR-K12-11-3p, that directly bind to STING1 mRNA to repress its translation and inhibit downstream immune signaling. Exogenous delivery of these KSHV miRNAs led to decreased STING expression and attenuated cGAS/STING signaling in response to STING agonist stimulation. Conversely, genetic deletion of these KSHV miRNAs rescued STING and interferon-stimulated gene expression in latent KSHV cell lines, delaying KSHV lytic reactivation and reducing KSHV lytic gene expression. These findings shed light on the immune evasion strategy of KSHV miRNA-mediated STING repression, representing the discovery of viral miRNAs that target STING.