Z-Nucleic Acid-Binding Protein (ZBP)1 (DAI/DLM1) Regulation in Antiviral Cell Death Pathways

Metazoan organisms employ an array of overlapping innate and adaptive immune mechanisms to defend against infection and prevent disease. Z-nucleic acid-binding protein (ZBP)1 (also denoted DAI or DLM1) has emerged as a key nucleic acid (NA) sensor within mammalian cells responding to stress, infection or inflammation. Once engaged and activated by Z-nucleic acid, ZBP1 recruits receptor-interacting protein (RIP) kinase (RIPK)3 through RIP homotypic interaction motif (RHIM)-mediated interactions to promote regulated cell death and inflammatory signaling, with necroptosis representing a particularly important antiviral defense mechanism. DNA viruses have coevolved with their hosts to encode diverse inhibitors that suppress ZBP1-RIPK3 signaling as well as other cell death pathways, highlighting the strong selective pressure imposed by necroptosis on viral replication. In contrast, RNA viruses lack inhibitors and activate multiple interconnected death pathways, including necroptosis, apoptosis, and pyroptosis. Increasing evidence indicates that both viral and cellular RNA transcripts adopt Z-conformation and activate ZBP1. Recent studies further implicate stress-induced transcriptional read-through, called disruption of transcription termination, of endogenous retroviral elements as important endogenous sources of Z-RNAs. These findings establish ZBP1 as a central sensor linking aberrant nucleic acid structures to RIPK3-dependent cell death and inflammation during viral infection and cellular stress of disease processes.