ZBP1: The Z-DNA Binding Protein 1 Transcript Variant 1 (G81030)

Target Name: ZBP1

NCBI ID: G81030

ZBP1

ZBP1: The Z-DNA Binding Protein 1 Transcript Variant 1

Introduction

Zinc-mediated regulation of gene expression is a crucial process in various biological processes, including DNA replication, repair, and gene splicing. Zinc ions are essential for the recruitment of chromatin-remodeling complexes, such as the ZBP1 complex, which play a pivotal role in ensuring the accuracy of DNA replication by altering the accessibility of gene promoters. The ZBP1 complex consists of the ZBP1 protein, p53, and other non-histone proteins that help to recruit DNA to the site of the Zn ion.

Recent studies have identified ZBP1 as a potential drug target and biomarker for various diseases, including cancer, neurodegenerative diseases, and autoimmune disorders. The ZBP1 gene has four alternative transcript variants, ZBP1-1, ZBP1-2, ZBP1-3, and ZBP1- 4, with different levels of expression in different tissues and conditions.

ZBP1-1, the most abundant transcript variant, is predominantly expressed in the brain, while ZBP1-2 and ZBP1-3 are mainly expressed in the liver and spleen, respectively. ZBP1-4 is expressed in the heart, kidneys, and testses. The expression patterns of these variants are regulated by various factors, including tissue-specific expression, translation efficiency, and post-transcriptional modifications, such as RNA-binding protein (RBP) modifications and phosphorylation modifications.

Expression and function of ZBP1

ZBP1 is a 22-kDa protein that contains a N-terminal transmembrane domain, a C-terminal Zn-binding domain, and a variable region that includes a G-Crichter at its amino-terminal end. The ZBP1 protein is involved in the regulation of gene expression by Zn2+, which can interact with its N-terminal domain to modulate its stability and localization to the nucleus.

Several studies have demonstrated that ZBP1 plays a critical role in regulating gene expression in various tissues and organs. For example, ZBP1 has been shown to be involved in the regulation of neuronal excitability and synaptic plasticity, and has been implicated in the development and progression of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

In addition to its role in gene regulation, ZBP1 has also been shown to play a structural and functional role in the Zn2+ signaling pathway. ZBP1 has a unique structure that allows it to interact with Zn2+ via multiple sites, including its N-terminal domain, C-terminal Zn-binding domain, and a binding site in the variable region. These interactions are critical for the regulation of Zn2+ signaling and the modulation of gene expression.

Drug targeting ZBP1

The ZBP1 protein has been identified as a potential drug target due to its involvement in various diseases, including cancer, neurodegenerative diseases, and autoimmune disorders. Several studies have suggested that inhibition of ZBP1 could be a promising strategy for treating these diseases.

One approach to targeting ZBP1 is the inhibition of its N-terminal domain, which is involved in the regulation of Zn2+ signaling and gene expression. Several studies have shown that inhibition of N-terminal domain activity can lead to decreased levels of ZBP1 protein and reduced gene expression, and that this effect is dose-dependent.

Another approach to targeting ZBP1 is the inhibition of its C-terminal Zn-binding domain, which is involved in the regulation of Zn2+ signaling and gene expression. Several studies have shown that inhibition of this domain can also lead to decreased levels of ZBP1 protein and reduced gene expression, and that this effect is dose-dependent.

In addition to inhibition of the N-terminal and C-terminal domains, some studies have also shown that inhibition of the ZBP1 protein itself can be effective in targeting ZBP1. This is achieved by preventing the formation of the ZBP1-DNA complex, which is critical for the regulation of gene expression by Zn2+.

Biomarker potential of ZBP1

The ZBP1 protein has been shown to play a critical role in various diseases, including cancer, neurodegenerative diseases, and autoimmune disorders. The ZBP1 gene has four alternative transcript variants, ZBP1-1, ZBP1-2, ZBP1-3, and ZBP1-4 , with different levels of expression in different tissues and conditions.

The expression patterns of these variants are regulated by various factors, including tissue-specific expression, translation efficiency, and post-transcriptional modifications, such as RBP

Protein Name: Z-DNA Binding Protein 1

Functions: Key innate sensor that recognizes and binds Z-RNA structures, which are produced by a number of viruses, such as herpesvirus, orthomyxovirus or flavivirus, and triggers different forms of cell death (PubMed:32200799). ZBP1 acts as an essential mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, by activating RIPK3, caspase-8 (CASP8), and the NLRP3 inflammasome (By similarity). Key activator of necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, via its ability to bind Z-RNA: once activated upon Z-RNA-binding, ZBP1 interacts and stimulates RIPK3 kinase, which phosphorylates and activates MLKL, triggering execution of programmed necrosis (By similarity). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: ZBP1 recognizes and binds Z-RNA structures that are produced in infected nuclei by orthomyxoviruses, such as the influenza A virus (IAV), leading to ZBP1 activation, RIPK3 stimulation and subsequent MLKL phosphorylation, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (PubMed:32200799). ZBP1-dependent cell death in response to IAV infection promotes interleukin-1 alpha (IL1A) induction in an NLRP3-inflammasome-independent manner: IL1A expression is required for the optimal interleukin-1 beta (IL1B) production, and together, these cytokines promote infiltration of inflammatory neutrophils to the lung, leading to the formation of neutrophil extracellular traps (By similarity). In addition to its direct role in driving necroptosis via its ability to sense Z-RNAs, also involved in PANoptosis triggered in response to bacterial infection: component of the AIM2 PANoptosome complex, a multiprotein complex that triggers PANoptosis (By similarity). Also acts as the apical sensor of fungal infection responsible for activating PANoptosis (By similarity). Involved in CASP8-mediated cell death via its interaction with RIPK1 but independently of its ability to sense Z-RNAs (By similarity). In some cell types, also able to restrict viral replication by promoting cell death-independent responses (By similarity). In response to Zika virus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with RIPK3, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate (By similarity). Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity)

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