ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis
Yi-Chieh Perng1, Jessica M C Warsaw2, Sachendra S Bais1
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Reports
|May 15, 2026
Summary
Interferon-stimulated gene 15 (ISG15) restrains necroptosis, a programmed inflammatory cell death. ISG15 deficiency exacerbates chikungunya virus (CHIKV) infection lethality by promoting necroptosis and inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Necroptosis, a programmed inflammatory cell death, is crucial for viral defense and inflammation.
- The RIPK3/MLKL pathway mediates necroptosis, but its regulation to prevent immunopathology is unclear.
Purpose of the Study:
- To investigate the role of interferon-stimulated gene 15 (ISG15) in regulating necroptosis and immunopathology during chikungunya virus (CHIKV) infection.
Main Methods:
- ISG15-deficient mice were infected with CHIKV.
- Necroptosis levels, cytokine/chemokine production, and lethality were assessed.
- RIPK3 and MLKL ablation were used to confirm the pathway.
Main Results:
- ISG15 deficiency led to increased necroptosis, elevated pro-inflammatory cytokines, and higher mortality in CHIKV-infected mice.
- Ablation of RIPK3 or MLKL prevented the exacerbated necroptosis and lethality in ISG15-deficient mice.
- ISG15 binds to the RIPK3 necrosome in a RHIM-dependent manner, regulating necroptosis.
Conclusions:
- ISG15 acts as a negative regulator of necroptosis, limiting immunopathology during CHIKV infection.
- Modulating ISG15-dependent necroptosis pathways offers a potential therapeutic strategy for viral infections and associated inflammation.
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