An Alternative Splicing of Tupaia STING Modulated Anti-RNA Virus Responses by Targeting MDA5-LGP2 and IRF3

The stimulator of IFN genes (STING; also known as MITA, TMEM173, MPYS, or ERIS) is generally regarded as a key adaptor protein for sensing pathogenic DNA genomes. However, its role in RNA viral signaling as part of the innate immunity system remains controversial. In this study, we identified two isoforms of STING (a full-length Tupaia STING [tSTING-FL] and a Tupaia STING short isoform [tSTING-mini]) in the Chinese tree shrew ( Tupaia belangeri chinensis ), a close relative of primates. tSTING-FL played a key role in the HSV-1-triggered type I IFN signaling pathway, whereas tSTING-mini was critical for RNA virus-induced antiviral signaling transduction. tSTING-mini, but not tSTING-FL, interacted with tMDA5-tLGP2 and tIRF3 in resting cells. Upon RNA virus infection, tSTING-mini caused a rapid enhancement of the tMDA5-tLGP2-mediated antiviral response and acted earlier than tSTING-FL. Furthermore, tSTING-mini was translocated from the cytoplasm to the nucleus during RNA virus infection and promoted tIRF3 phosphorylation through tSTING-mini-tIRF3 interaction, leading to a restriction of viral replication. After the initiation of antiviral effect, tSTING-mini underwent rapid degradation by tDTX3L-tPAPR9 via k48-linked ubiquitination through a proteasome-dependent pathway. Our results have shown alternative isoforms of STING counteract RNA virus infection in different ways.