DegronMD - Q9H171(ZBP1)

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: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). {ECO:0000250|UniProtKB:Q9QY24, ECO:0000269|PubMed:32200799}.; FUNCTION: (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. {ECO:0000269|PubMed:33348174}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.L396M	TCGA-22-A5C4	LUSC	TCGA	LTPKLE	DEG_SCF_FBW7_2	392:397	Mutation altering degron motif	0.5999
p.R374I	TCGA-AN-A046	BRCA	TCGA	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.0556
p.R379Q	TCGA-DA-A1HY	SKCM	TCGA	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.1944
p.F385C	DO229010	COCA	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7108
p.F385C	DO229013	COCA	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7108
p.F385C	DO229016	COCA	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7108
p.F385C	DO229003	COCA	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7108
p.F385C	DO229005	COCA	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7108
p.S377L	DO15870	HNSC	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.1389
p.P374S	DO222527	MELA	ICGC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.0556
p.A407V	DO232224	PBCA	ICGC	LTPKLE	DEG_SCF_FBW7_2	392:397	Mutation substituting flanking lysine	0.1667
p.H406P	SIDM00545	Melanoma	GDSC	LTPKLE	DEG_SCF_FBW7_2	392:397	Mutation rewiring degron network	0.0833
p.H406P	ACH-000987	Skin Cancer	CCLE	LTPKLE	DEG_SCF_FBW7_2	392:397	Mutation rewiring degron network	0.0833
p.H406P	Mewo	skin	COSMIC	LTPKLE	DEG_SCF_FBW7_2	392:397	Mutation rewiring degron network	0.0833
p.H376R	SIDM00746	Non-Small Cell Lung Carcinoma	GDSC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.1111
p.H376R	ACH-000766	Lung Cancer	CCLE	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.1111
p.H376R	NCI-H1648	lung	COSMIC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation rewiring degron network	0.1111
p.S390L	SIDM01578	Bladder Carcinoma	GDSC	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7667
p.S390L	ACH-000862	Bladder Cancer	CCLE	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.7667
p.S388R	ACH-001443	Thyroid Cancer	CCLE	PITPSHS	DEG_SCF_FBW7_1	384:390	Mutation altering degron motif	0.6316

Kaplan plot for ZBP1 in

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*NOTE: the Kaplan plots were collected from OncoLnc

DegronMD: protein-targeted degradation, mutation and drug response to degrons

ZBP1

UniProt ID: Q9H171

Entrez ID: 81030

Protein name: Z-DNA-binding protein 1 (DNA-dependent activator of IFN-regulatory factors) (DAI) (Tumor stroma and activated macrophage protein DLM-1)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for ZBP1 in