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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月21日

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  • Jian Deng,
  • Sheng-Nan Zheng,
  • Jing Zhang,
  • Cheng-Hao Li,
  • Tao Li,
  • Pei-Hui Wang

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.