GENTAUR Molecular Products.

 ZC12A_RAT               Reviewed;         596 AA.
 A0JPN4;
 10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
 12-DEC-2006, sequence version 1.
 13-FEB-2019, entry version 79.
 RecName: Full=Endoribonuclease ZC3H12A {ECO:0000305};
          EC=3.1.-.- {ECO:0000250|UniProtKB:Q5D1E7};
 AltName: Full=Monocyte chemotactic protein-induced protein 1 {ECO:0000250|UniProtKB:Q5D1E7};
          Short=MCP-induced protein 1 {ECO:0000250|UniProtKB:Q5D1E7};
          Short=MCPIP-1 {ECO:0000250|UniProtKB:Q5D1E7};
 AltName: Full=Regnase-1 {ECO:0000250|UniProtKB:Q5D1E7};
          Short=Reg1 {ECO:0000250|UniProtKB:Q5D1E7};
 AltName: Full=Zinc finger CCCH domain-containing protein 12A {ECO:0000312|RGD:1306776};
 Name=Zc3h12a {ECO:0000312|RGD:1306776};
 Rattus norvegicus (Rat).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
 Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
 Muroidea; Muridae; Murinae; Rattus.
 NCBI_TaxID=10116;
 [1] {ECO:0000312|EMBL:AAI27517.1}
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
 TISSUE=Heart {ECO:0000312|EMBL:AAI27517.1};
 PubMed=15489334; DOI=10.1101/gr.2596504;
 The MGC Project Team;
 "The status, quality, and expansion of the NIH full-length cDNA
 project: the Mammalian Gene Collection (MGC).";
 Genome Res. 14:2121-2127(2004).
 -!- 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. 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). 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). 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 (By similarity).
     Plays a role in the inhibition of microRNAs (miRNAs) biogenesis
     (By similarity). 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 (By similarity).
     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 (By
     similarity). Affects the overall ubiquitination of cellular
     proteins. 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. 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 (By similarity). Prevents stress granules (SGs) formation
     and promotes macrophage apoptosis under stress conditions,
     including arsenite-induced oxidative stress, heat shock, and
     energy deprivation. Plays a role in the regulation of macrophage
     polarization; promotes IL4-induced polarization of macrophages M1
     into anti-inflammatory M2 state. May also act as a transcription
     factor that regulates the expression of multiple genes involved in
     inflammatory response, angiogenesis, adipogenesis and apoptosis
     (By similarity). Functions as a positive regulator of glial
     differentiation of neuroprogenitor cells through an amyloid
     precursor protein (APP)-dependent signaling pathway (By
     similarity). 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).
     {ECO:0000250|UniProtKB:Q5D1E7, ECO:0000250|UniProtKB:Q5D1E8}.
 -!- COFACTOR:
     Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
       Evidence={ECO:0000250|UniProtKB:Q5D1E7};
     Note=Mg(2+) is required for RNase activity.
     {ECO:0000250|UniProtKB:Q5D1E7};
 -!- SUBUNIT: Oligomer. Found in a deubiquitination complex with TANK,
     USP10 and ZC3H12A; this complex inhibits genotoxic stress- or
     interleukin-1-beta-mediated NF-kappaB activation by promoting
     IKBKG or TRAF6 deubiquitination. Interacts with IKBKG; this
     interaction increases in response to DNA damage. Interacts with
     TANK; this interaction increases in response to DNA damage and
     serves as a bridge to anchor both TANK and USP10 into a
     deubiquitinating complex. Interacts with TRAF6; this interaction
     increases in response to DNA damage and is stimulated by TANK.
     Interacts with USP10; this interaction increases in response to
     DNA damage and serves as a bridge to anchor both TANK and USP10
     into a deubiquitinating complex. Interacts with ZC3H12D. 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. {ECO:0000250|UniProtKB:Q5D1E7,
     ECO:0000250|UniProtKB:Q5D1E8}.
 -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q5D1E7}.
     Cytoplasm {ECO:0000250|UniProtKB:Q5D1E7}. Rough endoplasmic
     reticulum membrane {ECO:0000250|UniProtKB:Q5D1E7}; Peripheral
     membrane protein {ECO:0000250|UniProtKB:Q5D1E7}; Cytoplasmic side
     {ECO:0000250|UniProtKB:Q5D1E7}. Cytoplasmic granule
     {ECO:0000250|UniProtKB:Q5D1E7}. Cytoplasm, P-body
     {ECO:0000250|UniProtKB:Q5D1E8}. 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). {ECO:0000250|UniProtKB:Q5D1E7,
     ECO:0000250|UniProtKB:Q5D1E8}.
 -!- DOMAIN: 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.
     {ECO:0000250|UniProtKB:Q5D1E8}.
 -!- PTM: 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. {ECO:0000250|UniProtKB:Q5D1E7}.
 -!- PTM: Ubiquitinated; ubiquitination is induced in response to
     interleukin IL1 receptor stimuli in a IKBKB/IKKB and IRAK1-
     dependent manner, leading to proteasome-mediated degradation.
     {ECO:0000250|UniProtKB:Q5D1E7}.
 -!- PTM: 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 and Th17 cell
     differentiation. {ECO:0000250|UniProtKB:Q5D1E7}.
 -!- SIMILARITY: Belongs to the ZC3H12 family. {ECO:0000305}.
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 EMBL; BC127516; AAI27517.1; -; mRNA.
 RefSeq; NP_001071139.1; NM_001077671.1.
 UniGene; Rn.234344; -.
 SMR; A0JPN4; -.
 STRING; 10116.ENSRNOP00000012314; -.
 iPTMnet; A0JPN4; -.
 PhosphoSitePlus; A0JPN4; -.
 PaxDb; A0JPN4; -.
 PRIDE; A0JPN4; -.
 Ensembl; ENSRNOT00000012314; ENSRNOP00000012314; ENSRNOG00000009131.
 GeneID; 313587; -.
 KEGG; rno:313587; -.
 UCSC; RGD:1306776; rat.
 CTD; 80149; -.
 RGD; 1306776; Zc3h12a.
 eggNOG; KOG3777; Eukaryota.
 eggNOG; ENOG410ZNK1; LUCA.
 GeneTree; ENSGT00940000155107; -.
 HOGENOM; HOG000060218; -.
 HOVERGEN; HBG108758; -.
 InParanoid; A0JPN4; -.
 KO; K18668; -.
 OMA; YWSEPYQ; -.
 OrthoDB; 771251at2759; -.
 PhylomeDB; A0JPN4; -.
 PRO; PR:A0JPN4; -.
 Proteomes; UP000002494; Chromosome 5.
 Bgee; ENSRNOG00000009131; Expressed in 9 organ(s), highest expression level in colon.
 Genevisible; A0JPN4; RN.
 GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
 GO; GO:0005856; C:cytoskeleton; ISS:UniProtKB.
 GO; GO:0042406; C:extrinsic component of endoplasmic reticulum membrane; ISS:UniProtKB.
 GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
 GO; GO:0005634; C:nucleus; ISS:UniProtKB.
 GO; GO:0000932; C:P-body; ISS:UniProtKB.
 GO; GO:0032991; C:protein-containing complex; ISS:UniProtKB.
 GO; GO:0005791; C:rough endoplasmic reticulum; ISS:UniProtKB.
 GO; GO:0030867; C:rough endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
 GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
 GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
 GO; GO:0004521; F:endoribonuclease activity; ISS:UniProtKB.
 GO; GO:0004532; F:exoribonuclease activity; ISS:UniProtKB.
 GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO; GO:0035198; F:miRNA binding; ISS:UniProtKB.
 GO; GO:0035925; F:mRNA 3'-UTR AU-rich region binding; ISS:UniProtKB.
 GO; GO:0003730; F:mRNA 3'-UTR binding; ISS:UniProtKB.
 GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
 GO; GO:0004518; F:nuclease activity; ISS:UniProtKB.
 GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
 GO; GO:0035613; F:RNA stem-loop binding; ISS:UniProtKB.
 GO; GO:0004843; F:thiol-dependent ubiquitin-specific protease activity; IEA:Ensembl.
 GO; GO:0061158; P:3'-UTR-mediated mRNA destabilization; ISS:UniProtKB.
 GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
 GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
 GO; GO:1990869; P:cellular response to chemokine; ISS:UniProtKB.
 GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
 GO; GO:0042149; P:cellular response to glucose starvation; IEA:Ensembl.
 GO; GO:0071347; P:cellular response to interleukin-1; IEA:Ensembl.
 GO; GO:1904637; P:cellular response to ionomycin; ISS:UniProtKB.
 GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:UniProtKB.
 GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl.
 GO; GO:1903936; P:cellular response to sodium arsenite; IEA:Ensembl.
 GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
 GO; GO:0098586; P:cellular response to virus; IEA:Ensembl.
 GO; GO:0002757; P:immune response-activating signal transduction; ISS:UniProtKB.
 GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
 GO; GO:0044828; P:negative regulation by host of viral genome replication; IEA:Ensembl.
 GO; GO:0055118; P:negative regulation of cardiac muscle contraction; ISS:UniProtKB.
 GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
 GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
 GO; GO:1902714; P:negative regulation of interferon-gamma secretion; ISS:UniProtKB.
 GO; GO:0050713; P:negative regulation of interleukin-1 beta secretion; ISS:UniProtKB.
 GO; GO:1900165; P:negative regulation of interleukin-6 secretion; ISS:UniProtKB.
 GO; GO:0010656; P:negative regulation of muscle cell apoptotic process; ISS:UniProtKB.
 GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
 GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
 GO; GO:0045019; P:negative regulation of nitric oxide biosynthetic process; ISS:UniProtKB.
 GO; GO:1903799; P:negative regulation of production of miRNAs involved in gene silencing by miRNA; ISS:UniProtKB.
 GO; GO:0001933; P:negative regulation of protein phosphorylation; IEA:Ensembl.
 GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB.
 GO; GO:1904468; P:negative regulation of tumor necrosis factor secretion; ISS:UniProtKB.
 GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
 GO; GO:0000294; P:nuclear-transcribed mRNA catabolic process, endonucleolytic cleavage-dependent decay; IEA:Ensembl.
 GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB.
 GO; GO:0010508; P:positive regulation of autophagy; IEA:Ensembl.
 GO; GO:0010942; P:positive regulation of cell death; ISS:UniProtKB.
 GO; GO:0002230; P:positive regulation of defense response to virus by host; IEA:Ensembl.
 GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB.
 GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IEA:Ensembl.
 GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
 GO; GO:0010884; P:positive regulation of lipid storage; IEA:Ensembl.
 GO; GO:2000627; P:positive regulation of miRNA catabolic process; ISS:UniProtKB.
 GO; GO:0061014; P:positive regulation of mRNA catabolic process; ISS:UniProtKB.
 GO; GO:1900745; P:positive regulation of p38MAPK cascade; IEA:Ensembl.
 GO; GO:1903003; P:positive regulation of protein deubiquitination; ISS:UniProtKB.
 GO; GO:0042307; P:positive regulation of protein import into nucleus; IEA:Ensembl.
 GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl.
 GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
 GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB.
 GO; GO:0016579; P:protein deubiquitination; IEA:Ensembl.
 GO; GO:0090501; P:RNA phosphodiester bond hydrolysis; ISS:UniProtKB.
 GO; GO:0090502; P:RNA phosphodiester bond hydrolysis, endonucleolytic; ISS:UniProtKB.
 GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB.
 InterPro; IPR040546; Rege-1_UBA-like.
 InterPro; IPR040757; Regnase_1/ZC3H12_C.
 InterPro; IPR021869; RNase_Zc3h12_NYN.
 Pfam; PF18561; Regnase_1_C; 1.
 Pfam; PF11977; RNase_Zc3h12a; 1.
 Pfam; PF18039; UBA_6; 1.
 2: Evidence at transcript level;
 Angiogenesis; Apoptosis; Complete proteome; Cytoplasm;
 Developmental protein; Differentiation; DNA damage; DNA-binding;
 Endonuclease; Endoplasmic reticulum; Hydrolase; Immunity;
 Inflammatory response; Magnesium; Membrane; Metal-binding;
 Neurogenesis; Nuclease; Nucleus; Phosphoprotein; Reference proteome;
 RNA-binding; Stress response; Ubl conjugation; Zinc; Zinc-finger.
 CHAIN         1    596       Endoribonuclease ZC3H12A.
                              /FTId=PRO_0000341514.
 ZN_FING     301    324       C3H1-type.
 REGION       42     87       Ubiquitin association domain.
                              {ECO:0000250|UniProtKB:Q5D1E7}.
 REGION       81    150       Necessary for interaction with TANK.
                              {ECO:0000250|UniProtKB:Q5D1E8}.
 REGION      112    281       RNase. {ECO:0000250|UniProtKB:Q5D1E8}.
 REGION      214    220       RNA binding.
                              {ECO:0000250|UniProtKB:Q5D1E8}.
 REGION      301    454       Necessary for interaction with ZC3H12D.
                              {ECO:0000250|UniProtKB:Q5D1E8}.
 COMPBIAS    496    533       Pro-rich. {ECO:0000255}.
 METAL       226    226       Magnesium.
                              {ECO:0000250|UniProtKB:Q5D1E8}.
 MOD_RES      99     99       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q5D1E8}.
 MOD_RES     344    344       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q5D1E8}.
 MOD_RES     435    435       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q5D1E7}.
 MOD_RES     439    439       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q5D1E7}.
 SEQUENCE   596 AA;  65927 MW;  C2BBA6DF323432AE CRC64;
 MSDPCGKKLV QEISPTMSLW GLEDRHSCQG QPQPDQDPVA KEASASELQM KVDFFRKLGY
 SSSEIHSALQ KLGVQADTNT VLGELVKHGS ATERECQAST DPCPQPPLVP RGGSTPKPST
 VEPSLPEEDK ESSDLRPVVI DGSNVAMSHG NKEVFSCRGI LLAVNWFLER GHTDITVFVP
 SWRKEQPRPD VPITDQHILR ELEKKKILVF TPSRRVGGKR VVCYDDRFIV KLAYESDGVV
 VSNDTYRDLQ GERQEWKRFI EERLLMYSFV NDKFMPPDDP LGRHGPSLDN FLRKKPLPSE
 HRKQPCPYGR KCTYGIKCRF FHPERPSRPQ RSVADELRAN ALLSPPRTPV KDKSSQRPSP
 ASQPNSMSLE AEPGSPDGKK LGTRSSPGPH QEGSTQTCAP AGRSLPVSGG SFGPTEWLPH
 TLDSLPYTSQ ECLDSGIGSL ESQMSELWGL RGGSPGESGP TRGPYTGYQT YGSKLPAAPA
 FSPFRQAIGT GHFSVPTDYV PPPPTYPARE YWSEPYPLPP PTPVLQEPQR PRPRASGDPW
 GRVSDLAKER AGVYTKLCGV FPPHLVEAVM GRFPQLLDPQ QLAAEILSYK SQHLSE

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