STING-ΔN, a novel splice isoform of STING, modulates innate immunity and autophagy in response to DNA virus infection

• Published in: Cell communication and signaling Vol. 23; no. 1; pp. 299 - 21
• Main Authors: Deng, Jian, Zheng, Sheng-Nan, Zhang, Jing, Li, Cheng-Hao, Li, Tao, Wang, Pei-Hui
• Format: Journal Article
• Language: English
• Published: England BioMed Central 21.06.2025; BMC
• Subjects: Adaptor proteins; Alternative Splicing; Amino acid sequence; Animals; Antibodies; Antiviral immunity; Autoimmune diseases; Autophagy; cGAS; Cytokines; Deoxyribonucleic acid; DNA; DNA Virus Infections - genetics; DNA Virus Infections - immunology; DNA Viruses; Gene regulation; HEK293 Cells; Herpes viruses; Herpesvirus 1, Human - physiology; HPV; Humans; Immune response; Immunity (Disease); Immunity, Innate; Immunoblotting; Immunofluorescence; Immunoprecipitation; Infections; Innate immunity; Interferon; Medical research; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nucleotidyltransferases - metabolism; Penicillin; Phosphorylation; Plaque assay; Plasmids; Post-transcription; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Serine-Threonine Kinases - metabolism; Proteins; Reagents; Signal Transduction; STING; STING-∆N; Therapeutic targets; Thymus gland; Viral infections; Alternative splicing; cGAS; STING; STING-∆N; Autophagy; Antiviral immunity; HPV
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-025-02305-w

Stimulator of interferon (IFN) genes (STING) is a central adaptor protein in the cGAS-STING signaling pathway, orchestrating the production of type I interferons (IFNs) in response to cytosolic DNA detection, a crucial mechanism in antiviral defense. However, further investigation is needed to understand how post-transcriptional regulation, particularly alternative splicing, modulates STING activity. We identified a novel alternatively spliced isoform of STING, termed STING-∆N, resulting from exon 3 skipping. We examined STING-∆N expression in various human tissues and cell lines and assessed its role in cGAS-STING signaling using RT-qPCR, luciferase reporter assays, SDD-AGE, immunofluorescence, and immunoblot analysis. We evaluated the influence of STING-∆N on HSV-1 proliferation and STING-induced autophagy by viral plaque assay and immunoblotting. To unravel the mechanistic role of STING-∆N, we further investigated its interaction with STING, TBK1, and 2'3'-cGAMP and its effect on the STING-TBK1 complex using co-immunoprecipitation and 2'3'-cGAMP pull-down assay. STING-∆N shares an identical C-terminal sequence (aa 121-379) with STING but lacks a 120-amino acid N-terminal region encoding three conserved transmembrane (TM) domains. STING-∆N is expressed in various human tissues and cell lines. STING-∆N significantly suppressed IFN activation induced by cGAS, 2'3'-cGAMP, and STING. STING-∆N also reduced type I and III IFN induction in response to double-stranded DNA, HPV, and HSV-1. Additionally, STING-∆N promoted HSV-1 replication and inhibited STING-induced autophagy. Mechanistically, STING-∆N interacts with 2'3'-cGAMP, STING, and TBK1, sequestering their binding and disrupting the formation of the 2'3'-cGAMP-STING and STING-TBK1 complexes. STING-∆N acts as a potent negative regulator of the cGAS-STING pathway, revealing a previously unrecognized regulatory mechanism by which alternative splicing modulates immune responses to DNA viruses. These findings suggest that STING-∆N could be a promising therapeutic target for modulating immune responses in viral infections, autoimmune diseases, and cancer.