A ZBP1 isoform blocks ZBP1-mediated cell death

ZBP1 is an interferon-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA), a type of left-handed nucleic acid. More than that, the binding of ZBP1 with Z-NA promotes cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppresser of the inflammatory signaling mediated by full-length ZBP1. Compared with ZBP1, ZBP1-S protein has Z domains but no RHIM domains. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Z domains of ZBP1. Cells from mice (Rip1D325A/D325A) with Cleavage-resistant RIP1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-depedent cell death. Intriguingly, Rip1D325A/D325A cells go death spontaneously when ZBP1-S was deleted, indicating the cell death driven by ZPB1 is under the check of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents an autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against auto-inflammations. HighlightO_LIZBP1-short isoform is expressed synchronously with ZBP1. C_LIO_LIZBP1-short isoform counteracts ZBP1 mediated cell death. C_LIO_LIZBP1-S suppresses ZBP1 signaling in an Z-domain dependent manner. C_LIO_LIZBP1-S prevents the autoactivation of ZBP1 in Rip1D325A/D325A cells. C_LI