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Updated: Jul 12, 2025
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Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
Published on: September 18, 2014
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Regulation of STING activity in DNA sensing by ISG15 modification
Chaohui Lin1, Edmund Osei Kuffour1, Nina V Fuchs2
1Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Cell Reports
|October 21, 2023
Summary
Interferon-stimulated gene 15 (ISG15) is essential for sensing human immunodeficiency virus type 1 (HIV-1) DNA via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. ISGylation of STING at K289 regulates its activation and viral DNA sensing.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway detects cytosolic DNA, including viral DNA, initiating innate immune responses.
- Post-translational modifications regulate cGAS-STING signaling, but their specific roles in sensing human immunodeficiency virus type 1 (HIV-1) remain incompletely understood.
Purpose of the Study:
- To investigate the role of interferon-stimulated gene 15 (ISG15) in cGAS-STING-dependent HIV-1 sensing.
- To elucidate the specific regulatory mechanisms of STING post-translational modification, particularly ISGylation, in antiviral immunity and autoimmune disorders.
Main Methods:
- Utilized ISG15-deficient cells and STING agonists to assess antiviral responses.
- Identified STING ISGylation sites using mass spectrometry.
- Investigated the impact of STING ISGylation inhibition on STING oligomerization and type I interferon induction.
- Employed molecular modeling to analyze the structural effects of ISGylation.
Main Results:
- ISG15 deficiency impaired STING-dependent sensing of HIV-1 DNA and STING agonist-induced antiviral responses.
- STING was found to be ISGylated at multiple residues, including K224, K236, K289, K347, K338, and K370.
- Inhibition of STING ISGylation at K289 suppressed type I interferon induction by preventing STING oligomerization.
- Removal of STING ISGylation alleviated the gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI).
Conclusions:
- ISG15 is a critical component of the cGAS-STING pathway for sensing HIV-1 DNA.
- STING ISGylation, particularly at K289, is a key regulatory mechanism controlling STING activation, oligomerization, and downstream immune signaling.
- Targeting STING ISGylation may offer therapeutic strategies for viral infections and autoimmune diseases like SAVI.
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