ZBP1 evolution and antagonism by large DNA viruses

ZBP1 is a nucleic acid receptor that restricts virus infection by activating an inflammatory gene response and by inducing host cell death. Left-handed Z-form nucleic acids accumulating in infected cells activate ZBP1 by binding to its N-terminal Zα domains. Signal transduction relies on the presence of RIP homotypic interaction motifs (RHIMs) that recruit the RIPK1 and RIPK3 signalling kinases to induce NF-κB activation or cell death under the forms of apoptosis or necroptosis. The expression of Zα domain proteins by poxviruses and RHIM-containing proteins by herpesviruses that antagonise ZBP1 may reflect a long-standing evolutionary interaction between ZBP1-mediated immunity and large DNA viruses. Phylogenetic analysis shows that ZBP1 likely emerged during jawed vertebrate speciation with ZBP1 orthologues first appearing in cartilaginous fish. ZBP1 is subsequently lost in entire vertebrate clades, including bony fish, scaled reptiles, birds, marsupials, and rabbits and hares, suggesting reoccurring counterselection of ZBP1-based immunity. Evidence of a ZBP1-like protein in distantly related bivalve molluscs indicates that sensing of Z-form nucleic acids coupled to RHIM-mediated signal transduction has evolved at least twice throughout the animal kingdom. Here, we study the origins, structure and function of ZBP1 and its Zα domains and RHIMs, discuss their respective roles in sensing Z-nucleic acids and signal transduction, and review ZBP1's mutually antagonistic relationship with large DNA viruses.