STING-∆C, a novel splice isoform of STING, inhibits DNA virus-induced innate immunity and autophagy.

Stimulator of interferon genes (STING) plays a critical role in the innate immune response to cytosolic DNA, primarily activating type I interferons (IFNs). Although alternative splicing is known to modulate immune pathways, the influence of STING splice isoforms requires further exploration. Here, we identified STING-∆C, a novel splice isoform of STING generated by retention of intron 6, resulting in a truncated C-terminus. While STING-∆C shares its N-terminal domain with full-length STING, it contains a unique C-terminal sequence. STING-∆C acts as a dominant negative regulator of cGAS-STING signaling pathway by suppressing cGAS-, 2'3'-cGAMP-, and STING-mediated activation of the IFN response. Gain- and loss-of-function experiments showed that STING-∆C inhibited IFN production in response to double-stranded DNA and DNA virus, including HSV-1 and HPV. Furthermore, STING-∆C promoted HSV-1 replication and reduces STING-induced autophagy. Mechanistically, STING-∆C interacts with full-length STING, preventing its oligomerization and assembly with TBK1, a vital component of the STING-TBK1-IRF3 signalsome. This interaction blocks IRF3 phosphorylation and nuclear translocation, thereby halting IFN production. STING-∆C thus represents a newly identified splice isoform that negatively regulates cGAS-STING signaling. These findings broaden our understanding of STING's regulatory mechanisms and may guide therapeutic strategies for autoimmune diseases and viral infections linked to excessive STING activation.