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.
Perng et al. (2026) studied this question.