DegronMD - Q5D1E8(ZC3H12A)

FUNCTION: Endoribonuclease involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis. Functions as an endoribonuclease involved in mRNA decay (PubMed:19909337). Modulates the inflammatory response by promoting the degradation of a set of translationally active cytokine-induced inflammation-related mRNAs, such as IL6 and IL12B, during the early phase of inflammation (PubMed:26320658). Prevents aberrant T-cell-mediated immune reaction by degradation of multiple mRNAs controlling T-cell activation, such as those encoding cytokines (IL6 and IL2), cell surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor (REL) (By similarity). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A (By similarity). Together with RC3H1, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (By similarity). Self regulates by destabilizing its own mRNA (By similarity). Cleaves mRNA harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-dependent manner (PubMed:19909337, PubMed:26320658, PubMed:26134560, PubMed:22561375). Plays a role in the inhibition of microRNAs (miRNAs) biogenesis (PubMed:22055188). Cleaves the terminal loop of a set of precursor miRNAs (pre-miRNAs) important for the regulation of the inflammatory response leading to their degradation, and thus preventing the biosynthesis of mature miRNAs (PubMed:22055188). Plays also a role in promoting angiogenesis in response to inflammatory cytokines by inhibiting the production of antiangiogenic microRNAs via its anti-dicer RNase activity (PubMed:24048733). Affects the overall ubiquitination of cellular proteins (By similarity). Positively regulates deubiquitinase activity promoting the cleavage at 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains on TNF receptor-associated factors (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation, and hence negatively regulating macrophage-mediated inflammatory response and immune homeostasis (By similarity). Induces also deubiquitination of the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes (PubMed:24048733). Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Prevents stress granule (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock and energy deprivation (By similarity). Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state (By similarity). May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (PubMed:16574901, PubMed:18364357). Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway (PubMed:19185603). Attenuates septic myocardial contractile dysfunction in response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase (IKK)-mediated NF-kappa-B activation, and hence myocardial pro-inflammatory cytokine production (By similarity). {ECO:0000250|UniProtKB:Q5D1E7, ECO:0000269|PubMed:16574901, ECO:0000269|PubMed:18364357, ECO:0000269|PubMed:19185603, ECO:0000269|PubMed:19909337, ECO:0000269|PubMed:22055188, ECO:0000269|PubMed:22561375, ECO:0000269|PubMed:24048733, ECO:0000269|PubMed:25861989, ECO:0000269|PubMed:26134560, ECO:0000269|PubMed:26320658}.; FUNCTION: (Microbial infection) Binds to Japanese encephalitis virus (JEV) and Dengue virus (DEN) RNAs. {ECO:0000269|PubMed:23355615}.; FUNCTION: (Microbial infection) Exhibits antiviral activity against HIV-1 in lymphocytes by decreasing the abundance of HIV-1 viral RNA species. {ECO:0000269|PubMed:24191027}. View more >>

GO - Biological processes (BP): 3'-UTR-mediated mRNA destabilization [GO:0061158]; angiogenesis [GO:0001525]; apoptotic process [GO:0006915]; cell differentiation [GO:0030154]; cellular response to chemokine [GO:1990869]; cellular response to DNA damage stimulus [GO:0006974]; cellular response to glucose starvation [GO:0042149]; cellular response to interleukin-1 [GO:0071347]; cellular response to ionomycin [GO:1904637]; cellular response to lipopolysaccharide [GO:0071222]; cellular response to oxidative stress [GO:0034599]; cellular response to sodium arsenite [GO:1903936]; cellular response to tumor necrosis factor [GO:0071356]; cellular response to virus [GO:0098586]; defense response to virus [GO:0051607]; immune response-activating signal transduction [GO:0002757]; inflammatory response [GO:0006954]; miRNA catabolic process [GO:0010587]; negative regulation by host of viral genome replication [GO:0044828]; negative regulation of cardiac muscle contraction [GO:0055118]; negative regulation of cytokine production involved in inflammatory response [GO:1900016]; negative regulation of gene expression [GO:0010629]; negative regulation of I-kappaB kinase/NF-kappaB signaling [GO:0043124]; negative regulation of interferon-gamma production [GO:0032689]; negative regulation of interleukin-1 beta production [GO:0032691]; negative regulation of interleukin-6 production [GO:0032715]; negative regulation of macrophage activation [GO:0043031]; negative regulation of muscle cell apoptotic process [GO:0010656]; negative regulation of NF-kappaB transcription factor activity [GO:0032088]; negative regulation of NIK/NF-kappaB signaling [GO:1901223]; negative regulation of nitric oxide biosynthetic process [GO:0045019]; negative regulation of production of miRNAs involved in gene silencing by miRNA [GO:1903799]; negative regulation of protein phosphorylation [GO:0001933]; negative regulation of T-helper 17 cell differentiation [GO:2000320]; negative regulation of tumor necrosis factor production [GO:0032720]; nervous system development [GO:0007399]; nuclear-transcribed mRNA catabolic process, endonucleolytic cleavage-dependent decay [GO:0000294]; positive regulation of angiogenesis [GO:0045766]; positive regulation of autophagy [GO:0010508]; positive regulation of cell death [GO:0010942]; positive regulation of defense response to virus by host [GO:0002230]; positive regulation of endothelial cell migration [GO:0010595]; positive regulation of execution phase of apoptosis [GO:1900119]; positive regulation of fat cell differentiation [GO:0045600]; positive regulation of gene expression [GO:0010628]; positive regulation of lipid storage [GO:0010884]; positive regulation of miRNA catabolic process [GO:2000627]; positive regulation of mRNA catabolic process [GO:0061014]; positive regulation of p38MAPK cascade [GO:1900745]; positive regulation of protein deubiquitination [GO:1903003]; positive regulation of protein import into nucleus [GO:0042307]; positive regulation of reactive oxygen species metabolic process [GO:2000379]; positive regulation of transcription by RNA polymerase II [GO:0045944]; protein complex oligomerization [GO:0051259]; protein deubiquitination [GO:0016579]; regulation of gene expression [GO:0010468]; RNA phosphodiester bond hydrolysis [GO:0090501]; RNA phosphodiester bond hydrolysis, endonucleolytic [GO:0090502]; T cell receptor signaling pathway [GO:0050852] View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.G439D	TCGA-06-0130	GBM	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.7198
p.G439D	DO12052	GBM	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.7198
p.S442P	TCGA-C5-A1MJ	CESC	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.6752
p.S442P	DO49017	CESC	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.6752
p.D434V	TCGA-CD-A4MG	STAD	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.25
p.D434V	DO48009	STAD	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.25
p.S438L	TCGA-D1-A17Q	UCEC	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.7667
p.S438L	TCGA-EO-A22R	UCEC	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.7667
p.S438L	DO41903	UCEC	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.7667
p.S438L	DO42713	UCEC	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.7667
p.L450F	TCGA-EI-6883	READ	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1111
p.L450F	DO36443	READ	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1111
p.E449Q	TCGA-GD-A76B	BLCA	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1389
p.E449Q	DO51886	BLCA	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1389
p.S448L	TCGA-IB-7651	PAAD	TCGA	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1667
p.S448L	DO46657	PAAD	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1667
p.M447I	DO229006	LICA	ICGC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1944
p.G439S	SIDM00477	Esophageal Carcinoma	GDSC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.6993
p.G439S	ACH-000383	Esophageal Cancer	CCLE	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.6993
p.G439S	OE33	oesophagus	COSMIC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation altering degron motif	0.6993
p.L436M	SIDM01619	Endometrial Carcinoma	GDSC	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.3056
p.L436M	ACH-000984	Endometrial/Uterine Cancer	CCLE	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.3056
p.M447R	ACH-001001	Bone Cancer	CCLE	DSGIGS	DEG_SCF_TRCP1_1	437:442	Mutation rewiring degron network	0.1944

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

ZC3H12A

UniProt ID: Q5D1E8

Entrez ID: 80149

Protein name: Endoribonuclease ZC3H12A (EC 3.1.-.-) (Monocyte chemotactic protein-induced protein 1) (MCP-induced protein 1) (MCPIP-1) (Regnase-1) (Reg1) (Zinc finger CCCH domain-containing protein 12A)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for ZC3H12A in