ZBP1
Description
The ZBP1 (Z-DNA binding protein 1) is a protein-coding gene located on chromosome 20.
Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene. ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding protein 1, a homolog of the human insulin-like growth factor 2 mRNA-binding protein 1 (IMP-1) and murine CRD-BP, the proteins involved in mRNA transport (RNA-binding proteins, RBPs).
== History == ZBP1 was first identified as an interferon-inducible Z-NA binding protein, but its specific functions remained unclear for many years. It was initially thought to be a cytosolic DNA sensor. However, the generation of Zbp1-deficient mice revealed that these mice responded normally to DNA and DNA virus infections, producing normal levels of interferon. Further insights came with the discovery of ZBP1's receptor-interacting protein homotypic interaction motif (RHIM) domains, which mediate interactions with other proteins. Experiments showed that ZBP1 interacts with RIPK1 and RIPK3 through these RHIM domains. This interaction hinted at ZBP1's involvement in cell death, especially given the role of RIPK proteins in cell death pathways. The role of ZBP1 as an innate immune sensor became more evident with the discovery that it regulates NLRP3 inflammasome activation and inflammatory cell death, PANoptosis, during influenza A virus infection. ZBP1-deficient mice showed impaired activation of inflammasome components, such as caspase-1, and reduced levels of IL-1β and IL-18, highlighting its critical role in antiviral defense.
ZBP1 is a key innate sensor that recognizes and binds Z-RNA structures produced by viruses like herpesvirus, orthomyxovirus, and flavivirus, triggering various forms of cell death. It acts as a crucial mediator of pyroptosis, necroptosis, and apoptosis (PANoptosis), a vital part of host defense against pathogens, by activating RIPK3, caspase-8 (CASP8), and the NLRP3 inflammasome. ZBP1 is a key activator of necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. It does this by binding Z-RNA, which then activates RIPK3 kinase. This leads to phosphorylation and activation of MLKL, ultimately triggering programmed necrosis. Beyond TNF-induced necroptosis, it can also occur in the nucleus in response to orthomyxoviruses. ZBP1 recognizes and binds Z-RNA structures produced in infected nuclei by orthomyxoviruses like influenza A virus (IAV), activating ZBP1, stimulating RIPK3, and phosphorylating MLKL, which disrupts the nuclear envelope and releases cellular DNA into the cytosol. ZBP1-dependent cell death in response to IAV infection promotes interleukin-1 alpha (IL1A) induction in an NLRP3-inflammasome-independent manner. IL1A expression is necessary for optimal interleukin-1 beta (IL1B) production. These cytokines promote inflammatory neutrophil infiltration into the lungs, leading to the formation of neutrophil extracellular traps. ZBP1 plays a direct role in driving necroptosis by sensing Z-RNAs. It is also involved in PANoptosis triggered by bacterial infection as a component of the AIM2 PANoptosome complex, a multiprotein complex that triggers PANoptosis. ZBP1 acts as the apical sensor of fungal infection, activating PANoptosis. It participates in CASP8-mediated cell death by interacting with RIPK1, independent of its ability to sense Z-RNAs. In some cell types, it restricts viral replication through cell death-independent responses. In response to Zika virus infection in neurons, it promotes a cell death-independent pathway that restricts viral replication. It works with RIPK3 to promote a death-independent transcriptional program that modifies cellular metabolism by upregulating the expression of the enzyme ACOD1/IRG1 and producing the metabolite itaconate. Itaconate inhibits succinate dehydrogenase, generating a metabolic state in neurons that suppresses the replication of viral genomes.
ZBP1 is also known as C20orf183, DAI, DLM-1, DLM1.
