Q9QY24 · ZBP1_MOUSE

  • Protein
    Z-DNA-binding protein 1
  • Gene
    Zbp1
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

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:17618271, PubMed:18375758, PubMed:19590578, PubMed:23283962, PubMed:27746097, PubMed:27819681, PubMed:27917412, PubMed:28607035, PubMed:28716805, PubMed:29073079, PubMed:30050136, PubMed:30498077, PubMed:31358656, PubMed:32200799, PubMed:32296175).
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).

Caution

According to a report, mice lacking Zbp1 display reductions in respiratory epithelial damage and lung inflammation (PubMed:27917412).
However, the virus persists and replicates in the infected cells leading to a delay in recovery from infection, but the animals are protected from mortality (PubMed:27917412).
In contrast, another article reported increased mortality in knockout mice, probably caused by increased virus burden (PubMed:27746097).
However, as this study did not assess the inflammatory response in the lungs, it is difficult to compare ZBP1 regulation of lung inflammation between these two studies (PubMed:27746097).

Activity regulation

ZBP1-dependent necroptosis is normally inhibited by RIPK1: RIPK1 inhibits the ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis.

GO annotations

AspectTerm
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentnucleus
Molecular FunctionDNA binding
Molecular Functiondouble-stranded RNA adenosine deaminase activity
Molecular Functiondouble-stranded RNA binding
Molecular Functionleft-handed Z-DNA binding
Biological Processactivation of innate immune response
Biological Processapoptotic process
Biological Processdefense response to fungus
Biological Processdefense response to virus
Biological Processinnate immune response
Biological Processpositive regulation of apoptotic process
Biological Processpositive regulation of inflammatory response
Biological Processpositive regulation of necroptotic process
Biological Processpositive regulation of type I interferon-mediated signaling pathway
Biological Processpyroptotic inflammatory response
Biological Processregulation of inflammatory response
Biological Processregulation of interleukin-1-mediated signaling pathway

Keywords

Community curation (1)

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.

SourceSubmission dateContributor
PubMed:341925170000-0002-3061-9942

Names & Taxonomy

Protein names

  • Recommended name
    Z-DNA-binding protein 1
  • Alternative names
    • DNA-dependent activator of IFN-regulatory factors
      (DAI
      )
    • Tumor stroma and activated macrophage protein DLM-1

Gene names

    • Name
      Zbp1
    • Synonyms
      Dlm1
Community curation (1)

Community suggested name: ZBP1

SourceSubmission dateContributor
PubMed:341925170000-0002-3061-9942

Organism names

  • Taxonomic identifier
  • Strains
    • C3Heb/FeJ
    • C57BL/6J
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q9QY24
  • Secondary accessions
    • Q8VE02
    • Q9D8B9

Proteomes

Organism-specific databases

Subcellular Location

Cytoplasm
Nucleus
Note: Mainly cytoplasmic (PubMed:32200799).
Accumulates in the nucleus in response to influenza A virus (IAV) infection: senses IAV defective viral genomes RNA in the nucleus (PubMed:32200799).

Keywords

Phenotypes & Variants

Disruption phenotype

Mice are resistant to necroptosis, characterized by a decrease in epithelial cell death and an increase in virus replication (PubMed:22423968, PubMed:27746097, PubMed:27917412).
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.

TypeIDPosition(s)Description
Mutagenesis46-50In 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.
Mutagenesis77-150Abolished ability to activate pyroptosis, necroptosis and apoptosis (PANoptosis) in response to influenza A virus (IAV) infection in knockin mice.
Mutagenesis122-126In 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.
Mutagenesis192-195In 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).
Mutagenesis248-251In mRHIMB; does not affect ability to induce necroptosis.
Mutagenesis352-353Does not greatly affect phosphorylation status.

PTM/Processing

Features

Showing features for chain, cross-link, modified residue (large scale data).

Type
IDPosition(s)Source
Description
ChainPRO_00000665651-411UniProtZ-DNA-binding protein 1
Cross-link17UniProtGlycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link43UniProtGlycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Modified residue (large scale data)356PTMeXchangePhosphothreonine
Modified residue (large scale data)368PTMeXchangePhosphoserine
Modified residue (large scale data)383PTMeXchangePhosphoserine
Modified residue (large scale data)384PTMeXchangePhosphoserine

Post-translational modification

Ubiquitinated; polyubiquitinated following influenza A virus (IAV) infection.
Phosphorylated.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Expressed in lung, spleen and liver. Lower levels were seen in heart, kidney and testis. Expression is greatly up-regulated in tumor stromal cells and activated macrophages.

Induction

Expression is activated by IRF1 (PubMed:29321274).
Up-regulated following interferon treatment (PubMed:10564822, PubMed:29073079).
By lipopolysaccharides (LPS) (PubMed:10564822).

Gene expression databases

Interaction

Subunit

Homodimer (PubMed:18375758).
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).
(Microbial infection) Interacts (via RIP homotypic interaction motif) with murid herpesvirus protein RIR1 (via RIP homotypic interaction motif); leading to inhibition of ZBP1-dependent necroptosis.
(Microbial infection) Interacts with vaccinia virus E3 protein; leading to inhibit ZBP1-dependent necroptosis.

Protein-protein interaction databases

Miscellaneous

Family & Domains

Features

Showing features for domain, region, motif, compositional bias.

Type
IDPosition(s)Description
Domain8-70Z-binding 1
Region60-86Disordered
Domain84-148Z-binding 2
Motif188-205RIP homotypic interaction motif (RHIM) 1
Motif237-261RIP homotypic interaction motif (RHIM) 2
Region263-303Disordered
Compositional bias268-292Polar residues
Region332-411Disordered
Compositional bias350-371Polar residues
Compositional bias400-411Polar residues

Domain

The Z-binding domains recognize and bind left-handed double-stranded Z-RNA structures, but not A-RNA, the right-handed double-stranded RNAs that are structurally very different from Z-RNAs (PubMed:32200799).
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

Phylogenomic databases

Family and domain databases

Sequence & Isoform

Align isoforms (2)
  • Sequence status
    Complete

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.

  • Length
    411
  • Mass (Da)
    44,331
  • Last updated
    2000-05-01 v1
  • MD5 Checksum
    4599A36797D4F5EE810C6684656B24FD
MAEAPVDLSTGDNLEQKILQVLSDDGGPVKIGQLVKKCQVPKKTLNQVLYRLKKEDRVSSPEPATWSIGGAASGDGAPAIPENSSAQPSLDERILRFLEANGPHRALHIAKALGMTTAKEVNPLLYSMRNKHLLSYDGQTWKIYHSRQEGQDIAHSGVTQESPAIICQHNPVNMICQQGANSHISIANSNAIQIGHGNVIVREKACGEPGPRTSHPLPLAWDASAQDMPPVAHGAQYIYMDKSLLQQVQLGHHNEMSLVGDAGKHPSYSFSDSPPEVSTTTADPGASFNMQTFEPGPHPEGDTVQTVHIKSCFLEDATIGNGNKMTIHLRSKGEVMESGDSEEPKKEDTGTSSEATPPRSCQHTPSDSMLPTSELRAMALGDSSPQTTEPVLREHEVQDIESSQDTGLSKQ

Q9QY24-2

  • Name
    2
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 154-187: AHSGVTQESPAIICQHNPVNMICQQGANSHISIA → VLPCSPGCPRTHHVDQAGLEPTEIFLLLPIKFWD
    • 188-411: Missing

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
A2APF7A2APF7_MOUSEZbp1411

Features

Showing features for sequence conflict, alternative sequence, compositional bias.

Type
IDPosition(s)Description
Sequence conflict67in Ref. 3; AAH20033
Sequence conflict83in Ref. 3; AAH20033
Alternative sequenceVSP_004083154-187in isoform 2
Alternative sequenceVSP_004084188-411in isoform 2
Sequence conflict197in Ref. 3; AAH20033
Compositional bias268-292Polar residues
Sequence conflict293in Ref. 3; AAH20033
Compositional bias350-371Polar residues
Compositional bias400-411Polar residues
Sequence conflict403in Ref. 3; AAH20033

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
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