Q9QY24 · ZBP1_MOUSE
- ProteinZ-DNA-binding protein 1
- GeneZbp1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids411 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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 (PubMed:27746097, PubMed:27917412, PubMed:28607035, PubMed:32200799, PubMed:32296175, PubMed:32298652, PubMed:32350114).
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 (PubMed:22423968, PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:28716805, PubMed:32200799, PubMed:32296175, PubMed:32315377, PubMed:32350114).
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, PubMed:32296175).
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 (PubMed:31630209).
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 (PubMed:34471287).
Also acts as the apical sensor of fungal infection responsible for activating PANoptosis (PubMed:33109609).
Involved in CASP8-mediated cell death via its interaction with RIPK1 but independently of its ability to sense Z-RNAs (PubMed:33397971).
In some cell types, also able to restrict viral replication by promoting cell death-independent responses (PubMed:30635240).
In response to flavivirus 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 (PubMed:30635240).
Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (PubMed:30635240).
Activity regulation
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | cytosol | |
Cellular Component | nucleus | |
Molecular Function | DNA binding | |
Molecular Function | double-stranded RNA adenosine deaminase activity | |
Molecular Function | double-stranded RNA binding | |
Molecular Function | left-handed Z-DNA binding | |
Biological Process | activation of innate immune response | |
Biological Process | apoptotic process | |
Biological Process | defense response to fungus | |
Biological Process | defense response to virus | |
Biological Process | innate immune response | |
Biological Process | positive regulation of apoptotic process | |
Biological Process | positive regulation of inflammatory response | |
Biological Process | positive regulation of necroptotic process | |
Biological Process | positive regulation of type I interferon-mediated signaling pathway | |
Biological Process | pyroptotic inflammatory response | |
Biological Process | regulation of inflammatory response | |
Biological Process | regulation of interleukin-1-mediated signaling pathway |
Keywords
- Molecular function
- Biological process
Community annotation
It is a specialized sensor for Z-RNA that is generated early during virus infection. Sensing of the Z-RNA PAMP activates virus-induced necroptosis resulting in early control of orthopoxvirus infection.
Source | Submission date | Contributor |
---|---|---|
PubMed:34192517 | ![]() |
Names & Taxonomy
Protein names
- Recommended nameZ-DNA-binding protein 1
- Alternative names
Gene names
Community suggested name: ZBP1
Source | Submission date | Contributor |
---|---|---|
PubMed:34192517 | ![]() |
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ9QY24
- Secondary accessions
Proteomes
Organism-specific databases
Phenotypes & Variants
Disruption phenotype
At a modestly lethal dose of influenza A virus (IAV), mice display significantly increased rates of mortality, probably caused by a failure to eliminate infected cells and limit virus spread in pulmonary tissue (PubMed:32200799).
Perinatal lethality observed in Ripk1 knockout mice is rescued in knockout mice lacking both Ripk1 and Zbp1 (PubMed:27819681, PubMed:27819682).
Skin inflammation observed in Ripk1(mRHIM) mutant mice is abrogated in Ripk1(mRHIM) mutant mice that also lack Zbp1 (PubMed:27819681).
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Mutagenesis | 46-50 | In ZBP1(Zalpha1); no effect. In ZBP1(Zalpha1-Zalpha2); knockin mice are viable and develop mild skin lesions in response to influenza A virus (IAV); mice are protected from the activation of RIPK3 and MLKL as well as the cell death; when associated with 122-D--A-126. | |||
Mutagenesis | 77-150 | Abolished ability to activate pyroptosis, necroptosis and apoptosis (PANoptosis) in response to influenza A virus (IAV) infection in knockin mice. | |||
Mutagenesis | 122-126 | In ZBP1(Zalpha2); abolished ability to sense influenza A virus (IAV) Z-RNAs. In ZBP1(Zalpha2); knockin mice are viable and develop mild skin lesions in response to influenza A virus (IAV). ZBP1(Zalpha2) knockin mice are protected from the activation of RIPK3 and MLKL as well as the cell death. In ZBP1(Zalpha1-Zalpha2); knockin mice are viable and develop mild skin lesions in response to influenza A virus (IAV); mice are protected from the activation of RIPK3 and MLKL as well as the cell death; when associated with 46-D--A-50. | |||
Mutagenesis | 192-195 | In mRHIMA; abolished interaction with RIPK3 and subsequent necroptosis. In ZBP1(Mr1) knockin mice are viable and do not develop skin inflammation in response to lethal dose of influenza A virus (IAV). | |||
Mutagenesis | 248-251 | In mRHIMB; does not affect ability to induce necroptosis. | |||
Mutagenesis | 352-353 | Does not greatly affect phosphorylation status. | |||
PTM/Processing
Features
Showing features for chain, cross-link, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | ||
---|---|---|---|---|---|---|
Chain | PRO_0000066565 | 1-411 | UniProt | Z-DNA-binding protein 1 | ||
Cross-link | 17 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | |||
Cross-link | 43 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | |||
Modified residue (large scale data) | 356 | PTMeXchange | Phosphothreonine | |||
Modified residue (large scale data) | 368 | PTMeXchange | Phosphoserine | |||
Modified residue (large scale data) | 383 | PTMeXchange | Phosphoserine | |||
Modified residue (large scale data) | 384 | PTMeXchange | Phosphoserine | |||
Post-translational modification
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Induction
Up-regulated following interferon treatment (PubMed:10564822, PubMed:29073079).
By lipopolysaccharides (LPS) (PubMed:10564822).
Gene expression databases
Interaction
Subunit
Interacts (via RIP homotypic interaction motif) with RIPK3; leading to RIPK3 activation and necroptosis; interaction is enhanced by CASP6 (PubMed:19590578, PubMed:22423968, PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:28607035, PubMed:32200799, PubMed:32298652).
Interacts (via RIP homotypic interaction motif) with RIPK1 (PubMed:19590578, PubMed:23283962, PubMed:33397971).
Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (PubMed:34471287).
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, motif, compositional bias.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Domain | 8-70 | Z-binding 1 | |||
Region | 60-86 | Disordered | |||
Domain | 84-148 | Z-binding 2 | |||
Motif | 188-205 | RIP homotypic interaction motif (RHIM) 1 | |||
Motif | 237-261 | RIP homotypic interaction motif (RHIM) 2 | |||
Region | 263-303 | Disordered | |||
Compositional bias | 268-292 | Polar residues | |||
Region | 332-411 | Disordered | |||
Compositional bias | 350-371 | Polar residues | |||
Compositional bias | 400-411 | Polar residues | |||
Domain
The second Z-binding domain (also named Zalpha2) acts as a molecular switch regulating pyroptosis, necroptosis and apoptosis (PANoptosis) (PubMed:32350114, PubMed:33109609).
The second Z-binding domain is essential for sensing influenza A virus (IAV) Z-RNAs (PubMed:28607035, PubMed:28716805, PubMed:32350114).
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q9QY24-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length411
- Mass (Da)44,331
- Last updated2000-05-01 v1
- MD5 Checksum4599A36797D4F5EE810C6684656B24FD
Q9QY24-2
- Name2
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A2APF7 | A2APF7_MOUSE | Zbp1 | 411 |
Features
Showing features for sequence conflict, alternative sequence, compositional bias.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Sequence conflict | 67 | in Ref. 3; AAH20033 | |||
Sequence conflict | 83 | in Ref. 3; AAH20033 | |||
Alternative sequence | VSP_004083 | 154-187 | in isoform 2 | ||
Alternative sequence | VSP_004084 | 188-411 | in isoform 2 | ||
Sequence conflict | 197 | in Ref. 3; AAH20033 | |||
Compositional bias | 268-292 | Polar residues | |||
Sequence conflict | 293 | in Ref. 3; AAH20033 | |||
Compositional bias | 350-371 | Polar residues | |||
Compositional bias | 400-411 | Polar residues | |||
Sequence conflict | 403 | in Ref. 3; AAH20033 | |||
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF136520 EMBL· GenBank· DDBJ | AAF17234.1 EMBL· GenBank· DDBJ | mRNA | ||
AK008179 EMBL· GenBank· DDBJ | BAB25513.1 EMBL· GenBank· DDBJ | mRNA | ||
BC020033 EMBL· GenBank· DDBJ | AAH20033.1 EMBL· GenBank· DDBJ | mRNA |