Ixodes scapularis STING promotes Powassan virus infection in ticks.

The stimulator of interferon genes (STING) is a central adaptor in antiviral signaling, but its role in vectors that transmit human and animal pathogens remains poorly understood. Here, we show that the tick STING homolog, tSTING, facilitates Powassan virus (POWV) infection in Ixodes scapularis -- in contrast to the canonical antiviral activity of mammalian STING. Transcriptomic and functional analyses revealed that tSTING regulates N-linked glycosylation and endocytosis, pathways essential for viral entry. Silencing of RPN2, a key glycosylation enzyme, significantly reduced viral loads, establishing a mechanistic link between tSTING and glycosylation-mediated viral uptake. Moreover, parallel studies in human THP-1 cells suggest human STING (hSTING) displays an opposite phenotype, restricting POWV replication potentially through OAS1-associated antiviral mechanisms independent of glycosylation. Together, these findings reveal an evolutionary reversal of STING function between arthropods and mammals, redefining the evolutionary logic of antiviral immunity across vector-host boundaries.