Zbp1, also known as Z-DNA-binding protein 1, DAI or DLM-1, is a critical innate immune sensor. It harbors nucleic acid-binding domains for left-handed helix (Z-form) and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein homotypic interactions [3]. Zbp1 is involved in detecting viral RNA products and endogenous nucleic acid ligands, regulating cell death (such as pyroptosis, apoptosis, necroptosis and PANoptosis), inflammasome activation, and pro-inflammatory responses [1,3]. It is also implicated in development, and dysregulation can lead to perinatal lethality [3]. Genetic models like KO/CKO mouse models are valuable for studying its functions.

In influenza virus infection, Zbp1 senses Z-RNA, recruiting RIPK3 and caspase-8 to activate the ZBP1-NLRP3 inflammasome, which is a key step in PANoptosis and PANoptosome assembly [1]. Influenza viral proteins can also regulate this inflammasome [1]. In another study, replicating influenza A virus generates Z-RNAs that activate Zbp1 in the nucleus, initiating RIPK3-mediated MLKL activation, leading to nuclear envelope disruption, DNA leakage, and necroptosis [2]. Mice lacking MLKL show reduced nuclear disruption, decreased neutrophil recruitment, and increased survival after a lethal dose of IAV [2]. In addition, Z-α-dependent sensing of endogenous ligands by Zbp1 induces perinatal lethality in mice with mutated RIPK1 RHIM, skin inflammation in RIPK1E-KO mice, and colitis in FADDIEC-KO mice [4]. Inhibition of nuclear export triggers Z-α-dependent RIPK3 activation in the nucleus, suggesting Zbp1 may recognize nuclear Z-form nucleic acids [4].

In conclusion, Zbp1 is an essential innate immune sensor regulating cell death and inflammation. Mouse models with Zbp1 KO/CKO have revealed its role in infectious diseases like influenza, as well as in conditions related to necroptosis and inflammation. Understanding Zbp1 functions through these models may help develop therapeutic strategies for infectious and inflammatory diseases.