A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis.

ABSTRACT: Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein NSs of a pathogenic hemorrhagic virus, SFTSV, interacts with the RIPK3 kinase domain and forms biocondensate to promote RIPK3 autophosphorylation and necroptosis activation in an RHIM-independent manner. In parallel, sequestration of RIPK3 within the NSs-RIPK3 condensate inhibited RIPK3-mediated apopto

SUBMITTER: Li S 

PROVIDER: S-EPMC12146775 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature