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Protein

Bifunctional endoribonuclease and deubiquitinase ZC3H12A

Gene

Zc3h12a

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

Bifunctional enzyme with both endoribonuclease and deubiquitinase activities 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. 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. 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). Self regulates by destabilizing its own mRNA. 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. Plays a role in the inhibition of microRNAs (miRNAs) biogenesis. 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. 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. Functions as a deubiquitinase that affects the overall ubiquitination of cellular proteins. Possesses deubiquitinase activity that specifically cleaves '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 regulates macrophage-mediated inflammatory response and immune homeostasis. Deubiquitinates also the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes. Prevents stress granules (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock, and energy deprivation, which may be dependent on its deubiquitinase activity. Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state, depending on both endoribonuclease and deubiquitinase activities. May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis. Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway. 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 proinflammatory cytokine production.By similarity

Catalytic activityi

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).By similarity

Cofactori

Mg2+By similarityNote: Mg2+ is required for RNase activity.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi226 – 2261MagnesiumBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri301 – 32424C3H1-typeAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Endonuclease, Hydrolase, Nuclease, Protease, Thiol protease

Keywords - Biological processi

Angiogenesis, Apoptosis, Differentiation, Immunity, Inflammatory response, Neurogenesis, Stress response, Ubl conjugation pathway

Keywords - Ligandi

DNA-binding, Magnesium, Metal-binding, RNA-binding, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
Bifunctional endoribonuclease and deubiquitinase ZC3H12ACurated
Including the following 2 domains:
Endoribonuclease ZC3H12ACurated (EC:3.1.-.-By similarity)
Deubiquitinase ZC3H12ACurated (EC:3.4.19.12By similarity)
Alternative name(s):
Monocyte chemotactic protein-induced protein 1By similarity
Short name:
MCP-induced protein 1By similarity
Short name:
MCPIP-1By similarity
Regnase-1By similarity
Short name:
Reg1By similarity
Zinc finger CCCH domain-containing protein 12AImported
Gene namesi
Name:Zc3h12aImported
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 5

Organism-specific databases

RGDi1306776. Zc3h12a.

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity
  • Rough endoplasmic reticulum membrane By similarity; Peripheral membrane protein By similarity; Cytoplasmic side By similarity
  • Cytoplasmic granule By similarity
  • CytoplasmP-body By similarity

  • Note: Predominantly localized in the cytoplasm. Colocalizes with GW182 on many granule-like structures, probably corresponding to cytoplasmic GW bodies (GWBs), also called processing bodies (P bodies). Colocalizes with calnexin on the surface of the rough endoplasmic reticulum (RER) membrane and with translationally active polysomes. Colocalizes with ZC3H12D in cytoplasmic mRNA processing P-body, also known as GW bodies (GWBs).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Membrane, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 596596Bifunctional endoribonuclease and deubiquitinase ZC3H12APRO_0000341514Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei99 – 991PhosphoserineBy similarity
Modified residuei344 – 3441PhosphoserineBy similarity
Modified residuei435 – 4351PhosphoserineBy similarity
Modified residuei439 – 4391PhosphoserineBy similarity

Post-translational modificationi

Proteolytically cleaved between Arg-111 and Arg-214 by MALT1 in activated T-cells; cleavage at Arg-111 is critical for promoting ZC3H12A degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling T-cell activation.By similarity
Phosphorylated by IRAK1; phosphorylation is necessary for subsequent phosphorylation by the I-kappa-B-kinase (IKK) complex. Phosphorylated by I-kappa-B-kinases (IKKs) at Ser-435 and Ser-439 upon lipopolysaccharide (LPS) or IL1B stimulation in macrophages through the MyD88-dependent signaling pathway; these phosphorylations promote rapid ubiquitin proteasome-mediated degradation of ZC3H12A in macrophages and hence allows its target mRNAs, such as IL6, to escape from degradation and accumulate during the inflammatory response.By similarity
Ubiquitinated; ubiquitination is induced in response to interleukin IL1 receptor stimuli in a IKBKB/IKKB and IRAK1-dependent manner, leading to proteasome-mediated degradation.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiA0JPN4.
PRIDEiA0JPN4.

PTM databases

iPTMnetiA0JPN4.
PhosphoSiteiA0JPN4.

Expressioni

Gene expression databases

BgeeiENSRNOG00000009131.
GenevisibleiA0JPN4. RN.

Interactioni

Subunit structurei

Oligomer. Interacts with ZC3H12D (By similarity). Interacts with TNRC6A. Interacts with IKBKB/IKKB. Interacts with IKBKB/IKKB. Interacts with IKBKB/IKKB. Interacts with BTRC; the interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner. Interacts with IRAK1; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB. Interacts with UPF1; this interaction occurs in a mRNA translationally active- and termination-dependent manner and is essential for ZC3H12A-mediated degradation of target mRNAs. Associates with ribosomes. Interacts with ubiquitin.By similarity

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000012314.

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 6363Deubiquitinase activityBy similarityAdd
BLAST
Regioni42 – 8746Ubiquitin association domainBy similarityAdd
BLAST
Regioni112 – 281170RNaseBy similarityAdd
BLAST
Regioni214 – 2207RNA bindingBy similarity
Regioni301 – 454154Necessary for interaction with ZC3H12DBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi496 – 53338Pro-richSequence analysisAdd
BLAST

Domaini

The C3H1-type zinc finger domain and C-terminal region are necessary for pre-miRNA binding. The C-terminal region and proline-rich domain are necessary for oligomerization.By similarity

Sequence similaritiesi

Belongs to the ZC3H12 family.Curated
Contains 1 C3H1-type zinc finger.By similarity

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri301 – 32424C3H1-typeAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3777. Eukaryota.
ENOG410ZNK1. LUCA.
GeneTreeiENSGT00750000117218.
HOGENOMiHOG000060218.
HOVERGENiHBG108758.
InParanoidiA0JPN4.
KOiK18668.
OMAiAFPPREY.
OrthoDBiEOG091G03B2.
PhylomeDBiA0JPN4.

Family and domain databases

InterProiIPR021869. RNase_Zc3h12_NYN.
[Graphical view]
PfamiPF11977. RNase_Zc3h12a. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

A0JPN4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSDPCGKKLV QEISPTMSLW GLEDRHSCQG QPQPDQDPVA KEASASELQM
60 70 80 90 100
KVDFFRKLGY SSSEIHSALQ KLGVQADTNT VLGELVKHGS ATERECQAST
110 120 130 140 150
DPCPQPPLVP RGGSTPKPST VEPSLPEEDK ESSDLRPVVI DGSNVAMSHG
160 170 180 190 200
NKEVFSCRGI LLAVNWFLER GHTDITVFVP SWRKEQPRPD VPITDQHILR
210 220 230 240 250
ELEKKKILVF TPSRRVGGKR VVCYDDRFIV KLAYESDGVV VSNDTYRDLQ
260 270 280 290 300
GERQEWKRFI EERLLMYSFV NDKFMPPDDP LGRHGPSLDN FLRKKPLPSE
310 320 330 340 350
HRKQPCPYGR KCTYGIKCRF FHPERPSRPQ RSVADELRAN ALLSPPRTPV
360 370 380 390 400
KDKSSQRPSP ASQPNSMSLE AEPGSPDGKK LGTRSSPGPH QEGSTQTCAP
410 420 430 440 450
AGRSLPVSGG SFGPTEWLPH TLDSLPYTSQ ECLDSGIGSL ESQMSELWGL
460 470 480 490 500
RGGSPGESGP TRGPYTGYQT YGSKLPAAPA FSPFRQAIGT GHFSVPTDYV
510 520 530 540 550
PPPPTYPARE YWSEPYPLPP PTPVLQEPQR PRPRASGDPW GRVSDLAKER
560 570 580 590
AGVYTKLCGV FPPHLVEAVM GRFPQLLDPQ QLAAEILSYK SQHLSE
Length:596
Mass (Da):65,927
Last modified:December 12, 2006 - v1
Checksum:iC2BBA6DF323432AE
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC127516 mRNA. Translation: AAI27517.1.
RefSeqiNP_001071139.1. NM_001077671.1.
XP_006238927.1. XM_006238865.2.
UniGeneiRn.234344.

Genome annotation databases

EnsembliENSRNOT00000012314; ENSRNOP00000012314; ENSRNOG00000009131.
GeneIDi313587.
KEGGirno:313587.
UCSCiRGD:1306776. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC127516 mRNA. Translation: AAI27517.1.
RefSeqiNP_001071139.1. NM_001077671.1.
XP_006238927.1. XM_006238865.2.
UniGeneiRn.234344.

3D structure databases

ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000012314.

PTM databases

iPTMnetiA0JPN4.
PhosphoSiteiA0JPN4.

Proteomic databases

PaxDbiA0JPN4.
PRIDEiA0JPN4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000012314; ENSRNOP00000012314; ENSRNOG00000009131.
GeneIDi313587.
KEGGirno:313587.
UCSCiRGD:1306776. rat.

Organism-specific databases

CTDi80149.
RGDi1306776. Zc3h12a.

Phylogenomic databases

eggNOGiKOG3777. Eukaryota.
ENOG410ZNK1. LUCA.
GeneTreeiENSGT00750000117218.
HOGENOMiHOG000060218.
HOVERGENiHBG108758.
InParanoidiA0JPN4.
KOiK18668.
OMAiAFPPREY.
OrthoDBiEOG091G03B2.
PhylomeDBiA0JPN4.

Miscellaneous databases

PROiA0JPN4.

Gene expression databases

BgeeiENSRNOG00000009131.
GenevisibleiA0JPN4. RN.

Family and domain databases

InterProiIPR021869. RNase_Zc3h12_NYN.
[Graphical view]
PfamiPF11977. RNase_Zc3h12a. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiZC12A_RAT
AccessioniPrimary (citable) accession number: A0JPN4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 10, 2008
Last sequence update: December 12, 2006
Last modified: September 7, 2016
This is version 62 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.