Z-DNA binding protein 1 (ZBP1) (ZBP1)

Z-DNA binding protein 1 (ZBP1), also known as DAI, is a critical cytosolic innate immune sensor that specifically recognizes the high-energy, left-handed Z-conformation of nucleic acids (Z-DNA and Z-RNA) [1]. It plays a pivotal role in detecting viral pathogens, such as influenza A virus, by sensing viral Z-RNA and triggering inflammatory signaling or programmed cell death pathways [2, 3]. Upon activation, ZBP1 recruits RIPK3 and other signaling molecules to initiate necroptosis, apoptosis, or pyroptosis (collectively termed PANoptosis), thereby eliminating infected cells [4]. Beyond its role in infection, ZBP1 can be activated by endogenous Z-DNA induced by cellular stress or small molecules like curaxins, making it a promising target in oncology for inducing immunogenic cell death in tumors [5]. However, dysregulated ZBP1 signaling is also a major driver of pathology in autoinflammatory diseases and chronic inflammation, where it mediates significant tissue damage [6]. Sources: [1] UniProt (Q9H171); [2] Kuriakose et al., Science Immunology (2016) 1(2):aag2671; [3] Zhang et al., Nature (2020) 580:392–396; [4] Kesavardhana et al., Nature (2020) 580:397–402; [5] Gurova et al., BioEssays (2018) 40(10):1800134; [6] Jiao et al., Nature (2020) 580:386–391.

Other names

DAIDLM-1DNA-dependent activator of IFN-regulatory factorsZ-DNA-binding protein 1

ZBP1 functions as a cytosolic sensor for left-handed Z-form nucleic acids. Small molecules such as curaxins (e.g., CBL0137) intercalate into the DNA double helix and induce a transition from B-DNA to Z-DNA. ZBP1 recognizes these Z-DNA structures via its N-terminal Zα domains, which triggers a conformational change and the recruitment of RIPK3 through RHIM-RHIM domain interactions. This assembly initiates downstream signaling pathways that lead to the production of type I interferons or the induction of programmed cell death, specifically necroptosis, via MLKL phosphorylation [1, 5].