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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
PubMed

Insights

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.
Keywords:
CHIKVCP: immunologyCP: microbiologyISG15MLKLRIPK3chikungunya virushomeostasisimmunopathologynecroptosis

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