ZBP1

Summary

ZBP1 (Z-DNA binding protein 1, HGNC:16176) is a protein-coding gene on chromosome 20q13.31, encoding Z-DNA-binding protein 1 (Q9H171). 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.

This gene encodes a Z-DNA binding protein. The encoded protein plays a role in the innate immune response by binding to foreign DNA and inducing type-I interferon production. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 81030 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 92 total
• MANE Select transcript: NM_030776

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16176
Approved symbol	ZBP1
Name	Z-DNA binding protein 1
Location	20q13.31
Locus type	gene with protein product
Status	Approved
Aliases	dJ718J7.3, DLM1, DLM-1, DAI
Ensembl gene	ENSG00000124256
Ensembl biotype	protein_coding
OMIM	606750
Entrez	81030

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000371173, ENST00000395822, ENST00000432548, ENST00000453793, ENST00000461547, ENST00000480037, ENST00000538947, ENST00000541799, ENST00000546110, ENST00000857153, ENST00000857154

RefSeq mRNA: 5 — MANE Select: NM_030776 NM_001160417, NM_001160418, NM_001160419, NM_001323966, NM_030776

CCDS: CCDS13461, CCDS54477, CCDS54478

Canonical transcript exons

ENST00000371173 — 8 exons

Exon	Start	End
ENSE00001252752	57620262	57620426
ENSE00003459133	57614887	57615060
ENSE00003536401	57616244	57616468
ENSE00003585528	57610149	57610367
ENSE00003625454	57611727	57611930
ENSE00003651355	57615512	57615580
ENSE00003684321	57613163	57613330
ENSE00003846476	57603852	57604769

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 95.41.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0921 / max 110.5676, expressed in 255 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188115	2.0182	229
188117	0.7026	163
188116	0.2038	99
188114	0.1675	85

Top tissues by expression

268 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	95.41	gold quality
buccal mucosa cell	CL:0002336	90.85	gold quality
blood	UBERON:0000178	88.74	gold quality
spleen	UBERON:0002106	85.93	gold quality
monocyte	CL:0000576	85.78	gold quality
leukocyte	CL:0000738	85.56	gold quality
mononuclear cell	CL:0000842	85.19	gold quality
lymph node	UBERON:0000029	84.68	gold quality
bone marrow cell	CL:0002092	83.03	gold quality
vermiform appendix	UBERON:0001154	82.85	gold quality
rectum	UBERON:0001052	82.18	gold quality
caecum	UBERON:0001153	80.39	gold quality
bone marrow	UBERON:0002371	80.18	gold quality
inferior olivary complex	UBERON:0002127	77.87	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	77.61	gold quality
gall bladder	UBERON:0002110	77.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.90	gold quality
colonic epithelium	UBERON:0000397	75.49	gold quality
tonsil	UBERON:0002372	75.31	gold quality
mucosa of transverse colon	UBERON:0004991	75.31	gold quality
tendon of biceps brachii	UBERON:0008188	74.99	gold quality
small intestine	UBERON:0002108	74.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.55	gold quality
parotid gland	UBERON:0001831	72.70	gold quality
duodenum	UBERON:0002114	72.70	gold quality
upper lobe of left lung	UBERON:0008952	72.54	gold quality
vastus lateralis	UBERON:0001379	72.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	72.17	gold quality
tongue squamous epithelium	UBERON:0006919	72.08	gold quality
right lung	UBERON:0002167	71.52	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	57.70
E-CURD-122	yes	45.21
E-HCAD-4	yes	43.07
E-ANND-3	yes	20.27
E-CURD-46	yes	19.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TCF7L2

miRNA regulators (miRDB)

14 targeting ZBP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-657	99.48	66.02	848
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6715B-3P	98.80	68.07	1204
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-339-5P	96.73	66.01	820
HSA-MIR-1231	95.10	65.63	663
HSA-MIR-758-5P	93.99	64.46	534

Literature-anchored findings (GeneRIF, showing 40)

• molecular cloning and structure analysis (PMID:11842111)
• Z-DNA binding activities of two Zalpha domains in the human ZBP1, hZalpha(ZBP1) and hZbeta(ZBP1)were characterized. (PMID:16448869)
• In conclusion, intracellular bacteria and cytosolic poly(dA-dT) activate IFNbeta responses in different human cells without requiring human ZBP1. (PMID:18771559)
• DAI binds to and colocalizes with endogenous adaptor receptor-interacting protein kinase (RIP)1 at characteristic cytoplasmic granules. (PMID:18941233)
• binding 2 DAIs to 1 dsDNA brings about dimerization of DAI that might facilitate DNA-mediated innate immune activation. (PMID:19095800)
• identify ZBP1 as being essential for IRF3 activation and interferon beta expression triggered by HCMV, as well as being sufficient to enhance HCMV-stimulated beta interferon transcription and secretion. (PMID:19846511)
• These results suggest that activation of DAI might contribute to augment HIV-1 replication through DAI- NF-kappaB pathway. (PMID:20599623)
• hZbeta(DAI) binds to Z-DNA via an active-di B-Z transition mechanism. (PMID:21296080)
• Solution structure of the Zbeta domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs. (PMID:21471454)
• Collectively, these results demonstrate that DAI can suppress HSV-1 growth independent of DNA sensing through mechanisms involving suppression of viral genomes and regulation of ICP0. (PMID:23283962)
• DAI could function as a DNA sensor and a regulator in DNA-induced macrophage M2b polarization and lupus nephritis. (PMID:23553627)
• Our results show that HSV2 is detected by a plethora of PRRs including DAI protein which trigger cytokine secretion to protect the host. (PMID:24080302)
• There is a correlation between the decrease in DAI-1 receptor expression and the severity of disease progression in preeclampsia. (PMID:29127557)
• this paper reviews the history and emergence of ZBP1 as a pathogen sensor and a central regulator of cell death and inflammatory responses (PMID:29236673)
• PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. (PMID:29581256)
• ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis). (PMID:33109609)
• The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma. (PMID:33596642)
• ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer. (PMID:33976222)
• Enrichment of Zalpha domains at cytoplasmic stress granules is due to their innate ability to bind to nucleic acids. (PMID:34037233)
• Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis. (PMID:34192517)
• AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence. (PMID:34471287)
• Viral Z-RNA triggers ZBP1-dependent cell death. (PMID:34688984)
• Oxidative stress induces Z-DNA-binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells. (PMID:34953858)
• TRIM34 modulates influenza virus-activated programmed cell death by targeting Z-DNA-binding protein 1 for K63-linked polyubiquitination. (PMID:35065966)
• Z-DNA binding protein 1 promotes heatstroke-induced cell death. (PMID:35511979)
• ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. (PMID:35614224)
• ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. (PMID:35859175)
• Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1. (PMID:36268590)
• Z-DNA/RNA Binding Protein 1 Senses Mitochondrial DNA to Induce Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like-Driven Necroptosis in Developmental Sevoflurane Neurotoxicity. (PMID:36370933)
• Fusobacterium nucleatum triggers proinflammatory cell death via Z-DNA binding protein 1 in apical periodontitis. (PMID:36539813)
• ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications. (PMID:36615244)
• ADAR1 and ZBP1 in innate immunity, cell death, and disease. (PMID:36710220)
• Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis. (PMID:36755096)
• PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis. (PMID:37267644)
• Z-form nucleic acid-binding protein 1 (ZBP1) as a sensor of viral and cellular Z-RNAs: walking the razor’s edge. (PMID:37276820)
• Heartbreakers: innate sensors ZBP1 and cGAS linked to cardiotoxicity. (PMID:37587292)
• Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1. (PMID:37725754)
• ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway. (PMID:38331384)
• The innovative checkpoint inhibitors of lung adenocarcinoma, cg09897064 methylation and ZBP1 expression reduction, have implications for macrophage polarization and tumor growth in lung cancer. (PMID:38369516)
• Sensing of mitochondrial DNA by ZBP1 promotes RIPK3-mediated necroptosis and ferroptosis in response to diquat poisoning. (PMID:38493248)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zbp1	ENSMUSG00000027514
rattus_norvegicus	Zbp1	ENSRNOG00000006314

Protein

Protein identifiers

Z-DNA-binding protein 1 — Q9H171 (reviewed: Q9H171)

Alternative names: DNA-dependent activator of IFN-regulatory factors, Tumor stroma and activated macrophage protein DLM-1

All UniProt accessions (2): Q9H171, H0Y6D1

UniProt curated annotations — full annotation on UniProt →

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. 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. Key activator of necroptosis, a programmed cell death process in response to death-inducing TNF 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. 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. 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. 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. Also acts as the apical sensor of fungal infection responsible for activating PANoptosis. Involved in CASP8-mediated cell death via its interaction with RIPK1 but independently of its ability to sense Z-RNAs. In some cell types, also able to restrict viral replication by promoting cell death-independent responses. 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. Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. (Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms hetero-amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit ZBP1-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion.

Subunit / interactions. Homodimer. Interacts (via RIP homotypic interaction motif) with RIPK3; leading to RIPK3 activation and necroptosis; interaction is enhanced by CASP6. Interacts (via RIP homotypic interaction motif) with RIPK1. Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis). (Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RHIM); this interaction may induce heteromeric amyloid assemblies and prevent necroptosis activation. Interacts with human herpes simplex virus 1/HHV-1 protein ICP0.

Subcellular location. Cytoplasm. Nucleus Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in lymphatic tissues including lymph node, leukocytes, tonsil, bone marrow and spleen. Expressed to a lesser extent in thymus, lung and liver.

Post-translational modifications. Phosphorylated.

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.

Domain organisation. 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. The second Z-binding domain (also named Zalpha2) acts as a molecular switch regulating pyroptosis, necroptosis and apoptosis (PANoptosis). The second Z-binding domain is essential for sensing influenza A virus (IAV) Z-RNAs. (Microbial infection) The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of the herpes simplex virus 1/HHV-1 protein RIR1/ICP6 to form hetero-amyloid structures.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9H171-1	1	yes
Q9H171-2	2
Q9H171-3	3
Q9H171-4	4
Q9H171-5	5
Q9H171-6	6
Q9H171-7	7, Delta-exon-2, Deltaexon-2, Delta-Z-alpha, DeltaZalpha

RefSeq proteins (5): NP_001153889, NP_001153890, NP_001153891, NP_001310895, NP_110403* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025735	RHIM	Binding_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR042361	ZBP1	Family
IPR042371	Z_dom	Domain

Pfam: PF02295, PF12721

UniProt features (39 total): splice variant 8, sequence variant 8, helix 7, strand 5, region of interest 3, domain 2, short sequence motif 2, compositionally biased region 2, chain 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3EYI	X-RAY DIFFRACTION	1.45
9J89	X-RAY DIFFRACTION	1.58
4KA4	X-RAY DIFFRACTION	2.6
2L4M	SOLUTION NMR
2LNB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H171-F1	54.02	0.14

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1606322	ZBP1(DAI) mediated induction of type I IFNs
R-HSA-1606341	IRF3 mediated activation of type 1 IFN
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-3134975	Regulation of innate immune responses to cytosolic DNA
R-HSA-9679191	Potential therapeutics for SARS

MSigDB gene sets: 274 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, ODONNELL_TARGETS_OF_MYC_AND_TFRC_UP, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_RESPONSE_TO_INTERLEUKIN_1, IRF_Q6

GO Biological Process (17): activation of innate immune response (GO:0002218), apoptotic process (GO:0006915), positive regulation of apoptotic process (GO:0043065), regulation of inflammatory response (GO:0050727), positive regulation of inflammatory response (GO:0050729), defense response to fungus (GO:0050832), defense response to virus (GO:0051607), positive regulation of type I interferon-mediated signaling pathway (GO:0060340), positive regulation of necroptotic process (GO:0060545), pyroptotic inflammatory response (GO:0070269), antiviral innate immune response (GO:0140374), regulation of interleukin-1-mediated signaling pathway (GO:2000659), immune system process (GO:0002376), programmed cell death (GO:0012501), innate immune response (GO:0045087), necroptotic signaling pathway (GO:0097527), execution phase of necroptosis (GO:0097528)

GO Molecular Function (7): DNA binding (GO:0003677), left-handed Z-DNA binding (GO:0003692), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), double-stranded RNA adenosine deaminase activity (GO:0003726), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cytosolic sensors of pathogen-associated DNA	2
ZBP1(DAI) mediated induction of type I IFNs	2
SARS-CoV Infections	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inflammatory response	3
necroptotic process	3
positive regulation of innate immune response	2
defense response	2
signal transduction	2
nucleic acid binding	2
cellular anatomical structure	2
activation of immune response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of defense response	1
regulation of response to external stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
response to fungus	1
response to virus	1
positive regulation of cytokine-mediated signaling pathway	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
regulation of necroptotic process	1
positive regulation of programmed necrotic cell death	1
innate immune response	1
defense response to virus	1
regulation of cytokine-mediated signaling pathway	1
interleukin-1-mediated signaling pathway	1
biological_process	1
cell death	1
immune response	1
defense response to symbiont	1
cellular process	1
double-stranded DNA binding	1
RNA binding	1
deaminase activity	1
protein binding	1
binding	1

Protein interactions and networks

STRING

739 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZBP1	RIPK1	Q13546	967
ZBP1	RIPK3	Q9Y572	957
ZBP1	IRF3	Q14653	892
ZBP1	TBK1	Q9UHD2	863
ZBP1	CASP8	Q14790	815
ZBP1	FADD	Q13158	700
ZBP1	MEFV	O15553	692
ZBP1	IFNB1	P01574	691
ZBP1	ADAR	P55265	687
ZBP1	MLKL	Q8NB16	669
ZBP1	IFI16	Q16666	626
ZBP1	IRF7	Q92985	621
ZBP1	TANK	Q92844	618
ZBP1	TLR9	Q9NR96	615
ZBP1	AIM2	O14862	614

IntAct

27 interactions, top by confidence:

A	B	Type	Score
ZBP1		psi-mi:“MI:0915”(physical association)	0.560
HTT	ZBP1	psi-mi:“MI:0915”(physical association)	0.560
AGO2	HNRNPA1	psi-mi:“MI:0914”(association)	0.480
RIPK1	ZBP1	psi-mi:“MI:0407”(direct interaction)	0.360
ZBP1	BCKDK	psi-mi:“MI:0914”(association)	0.350
ZBP1	KRR1	psi-mi:“MI:0914”(association)	0.350
KRR1	ZBP1	psi-mi:“MI:0914”(association)	0.350
RIPK3	ZBP1	psi-mi:“MI:0914”(association)	0.350
ZBP1	RIPK3	psi-mi:“MI:0914”(association)	0.350
ZBP1	M45	psi-mi:“MI:0914”(association)	0.350
AGO1	HNRNPA1	psi-mi:“MI:0914”(association)	0.350
RBM15	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
SMNDC1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SUPV3L1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
TBRG4	VWA8	psi-mi:“MI:2364”(proximity)	0.270
NSUN2	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (54): ZBP1 (Two-hybrid), ZBP1 (Two-hybrid), ZBP1 (Two-hybrid), BCKDHA (Affinity Capture-MS), BCKDK (Affinity Capture-MS), MDH2 (Affinity Capture-MS), NSA2 (Affinity Capture-MS), ZNF740 (Affinity Capture-MS), ZBP1 (Proximity Label-MS), ZBP1 (Affinity Capture-MS), ZBP1 (Affinity Capture-MS), ZBP1 (Affinity Capture-MS), ZBP1 (Affinity Capture-MS), ZBP1 (Affinity Capture-MS), ZBP1 (Biochemical Activity)

ESM2 similar proteins: O09139, O35254, O35261, O54943, O94966, O95238, P59729, Q01094, Q14209, Q16254, Q1LVK9, Q4JF29, Q5SW75, Q5XIS1, Q61501, Q6A037, Q6P1D7, Q6ZQF7, Q6ZRS4, Q76I76, Q76I79, Q76N89, Q7TSI1, Q80U38, Q80UF7, Q8BLR5, Q8IUC6, Q8K330, Q8K3T2, Q8TB24, Q8TE77, Q8VDA5, Q8WYL5, Q90977, Q91V27, Q91X51, Q9BQQ3, Q9BV36, Q9C0D6, Q9D2Q3

Diamond homologs: Q8VDA5, Q9H171, Q9QY24

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ZBP1	“up-regulates activity”	RIPK3	binding
Z-RNA	“up-regulates activity”	ZBP1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

92 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1821 predictions. Top by Δscore:

Variant	Effect	Δscore
20:57604769:CCTAG:C	acceptor_loss	1.0000
20:57604770:C:CC	acceptor_gain	1.0000
20:57604771:T:A	acceptor_loss	1.0000
20:57613158:CTTA:C	donor_loss	1.0000
20:57613160:TACC:T	donor_loss	1.0000
20:57613161:A:AC	donor_gain	1.0000
20:57613161:AC:A	donor_gain	1.0000
20:57613161:ACCGT:A	donor_gain	1.0000
20:57613162:C:CC	donor_gain	1.0000
20:57613162:CC:C	donor_gain	1.0000
20:57613162:CCGTC:C	donor_gain	1.0000
20:57613328:CTT:C	acceptor_gain	1.0000
20:57613331:C:CC	acceptor_gain	1.0000
20:57615061:C:CC	acceptor_gain	1.0000
20:57615505:AACTT:A	donor_loss	1.0000
20:57615506:ACTT:A	donor_loss	1.0000
20:57615507:CTTA:C	donor_loss	1.0000
20:57615508:TTA:T	donor_loss	1.0000
20:57615509:TACC:T	donor_loss	1.0000
20:57615510:A:AC	donor_gain	1.0000
20:57615510:A:AG	donor_loss	1.0000
20:57615510:AC:A	donor_gain	1.0000
20:57615510:ACC:A	donor_gain	1.0000
20:57615511:C:CC	donor_gain	1.0000
20:57615511:CC:C	donor_gain	1.0000
20:57615511:CCC:C	donor_gain	1.0000
20:57615511:CCCCG:C	donor_gain	1.0000
20:57615576:CTCGG:C	acceptor_gain	1.0000
20:57615577:TCGG:T	acceptor_gain	1.0000
20:57615578:CGG:C	acceptor_gain	1.0000

AlphaMissense

2810 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:57614905:A:G	W162R	0.993
20:57614905:A:T	W162R	0.993
20:57614958:A:G	L144S	0.993
20:57615003:G:T	A129D	0.988
20:57616307:A:G	W66R	0.987
20:57616307:A:T	W66R	0.987
20:57615006:A:T	I128N	0.985
20:57614903:C:A	W162C	0.983
20:57614903:C:G	W162C	0.983
20:57614949:A:G	M147T	0.983
20:57615039:A:G	L117P	0.981
20:57616305:C:A	W66C	0.979
20:57616305:C:G	W66C	0.979
20:57615004:C:G	A129P	0.976
20:57615006:A:C	I128S	0.976
20:57615039:A:T	L117H	0.976
20:57614958:A:C	L144W	0.974
20:57616450:A:G	I18T	0.973
20:57616357:A:T	L49H	0.970
20:57613197:G:C	N212K	0.967
20:57613197:G:T	N212K	0.967
20:57614948:C:A	M147I	0.967
20:57614948:C:G	M147I	0.967
20:57614948:C:T	M147I	0.967
20:57614931:A:T	L153Q	0.966
20:57614970:A:T	V140E	0.965
20:57616369:A:T	L45H	0.964
20:57614904:C:G	W162S	0.962
20:57611791:A:C	N270K	0.957
20:57611791:A:T	N270K	0.957

dbSNP variants (sampled 300 via entrez): RS1000113327 (20:57614479 C>A), RS1000318221 (20:57618943 G>A), RS1000602243 (20:57617934 C>A), RS1000676924 (20:57619185 G>A,T), RS1000804787 (20:57611145 G>C), RS1000938345 (20:57620967 C>T), RS1000968962 (20:57605306 C>T), RS1000973505 (20:57606326 G>A), RS1001056048 (20:57617685 C>T), RS1001271076 (20:57607340 A>T), RS1001634338 (20:57607896 C>A,T), RS1001733055 (20:57620090 C>T), RS1001976391 (20:57606651 C>T), RS1002028935 (20:57606308 G>C), RS1002182175 (20:57611004 C>T)

Disease associations

OMIM: gene MIM:606750 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000461_15	Hippocampal atrophy	2.000000e-06
GCST001738_1	Response to fenofibrate (adiponectin levels)	2.000000e-07
GCST002701_33	Verbal declarative memory	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005039	hippocampal atrophy
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
CBLC137	increases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
aflatoxin B2	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
2-ethylhexyl 2,3,4,5-tetrabromobenzoate	increases expression, decreases reaction	1
Air Pollutants	increases abundance, increases expression	1
Ethidium	decreases reaction, increases expression	1
Nickel	increases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Zinc	increases expression	1
Sodium Selenite	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.