2. Academic Validation
  3. ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis

ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis

  • Cell Rep. 2026 May 26;45(5):117360. doi: 10.1016/j.celrep.2026.117360.
Yi-Chieh Perng 1,  Jessica M C Warsaw 2,  Sachendra S Bais 1,  Bradley E Hiller 3,  Marissa C Locke 4,  David J Morales-Heil 1,  Chaoqun Li 5,  Alissa R Young 3,  Kristen J Monte 1,  Robert E Schmidt 4,  Douglas R Green 6,  Yi-Nan Gong 7,  Deborah J Lenschow 8
Affiliations

Affiliations

  • 1 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 5 Department of Immunology, University of Pittsburgh School of Medicine, Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
  • 6 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 7 Department of Immunology, University of Pittsburgh School of Medicine, Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. Electronic address: [email protected].
  • 8 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected].
PMID: 42139056 DOI: 10.1016/j.celrep.2026.117360
Abstract

Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/Mixed Lineage Kinase domain-like pseudokinase (MLKL) pathway mediates Necroptosis. Yet, the mechanisms that control Necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including Necroptosis, and limits immunopathology during chikungunya virus (CHIKV) Infection. ISG15-deficient mice infected with CHIKV display increased levels of Necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated in Isg15-/- mice. Mechanistically, ISG15 non-covalently associates with the RIPK3 necrosome in an RIP homotypic interaction motif (RHIM)-dependent manner, regulating Necroptosis downstream of CHIKV Infection, tumor necrosis factor (TNF), lipopolysaccharide (LPS), and poly(I:C) stimulation. These results demonstrate a role for ISG15 in limiting immunopathology during Infection by modulating necroptosis-dependent inflammation and pathogenesis.

Keywords

CHIKV; CP: immunology; CP: microbiology; ISG15; MLKL; RIPK3; chikungunya virus; homeostasis; immunopathology; necroptosis.

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