ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis
Year: 2026
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: University of California-San Diego, Walter and Eliza Hall Institute, National Institutes of Health, Genentech, Musculoskeletal Research Center, Washington University in St. Louis, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Rheumatic Diseases Research Resource-Based Center, Washington University School of Medicine in St. Louis
Awards: G1416977237, G2000294849, G2352575307, G2566998440, G2576474147, G304139194, G741073515, Washington University Rheumatic Diseases Research Resource-based Center, Infectious Disease/Basic Microbial Pathogenic Mechanisms, TRAINING IN THE IMMUNOBIOLOGY AND MOLECULAR CELL BIOLOGY OF CANCER, Interferon-Stimulated Gene 15 as a Novel Regulator of Cell Death DuringAcute Kidney Injury
OpenAlex ID: W7161294556