Abstract
Necroptosis mediated by Z-nucleic acid binding protein (ZBP)1 (also known as DAI and DLM1) provides innate host defense against viruses. Unless blocked by vaccinia virus (VACV) protein E3, ZBP1 triggers RIP-homotypic interaction motif (RHIM)-dependent activation of RIPK3 to execute cell death, cut short replication and limit pathogenesis. Here, Z-form RNA is shown to be sequestered in the cytoplasm dependent on the Z-nucleic acid binding domain of E3. Mutating the Zα motif within this domain permits accumulation of free Z-RNA during the early phase of VACV infection that triggers ZBP1-mediated VACV-induced necroptosis. Zα from either ZBP1 or the RNA editing enzyme double-stranded RNA adenosine deaminase (ADAR)1 are functionally interchangeable with E3 Zα and suffice to block virus-induced necroptosis as a component of chimeric viruses. Overall, the evidence shows that Z-form RNA generated during VACV infection unleashes ZBP1-RIPK3-dependent necroptosis and unveils the mechanism through which viral E3 suppresses sensing of this PAMP.
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