ZC12A_BOVIN
ID ZC12A_BOVIN Reviewed; 583 AA.
AC A6QQJ8;
DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
DT 21-AUG-2007, sequence version 1.
DT 03-AUG-2022, entry version 92.
DE RecName: Full=Ribonuclease ZC3H12A;
DE EC=3.1.-.-;
DE AltName: Full=Zinc finger CCCH domain-containing protein 12A;
GN Name=ZC3H12A {ECO:0000250|UniProtKB:Q5D1E8};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1] {ECO:0000312|EMBL:AAI49868.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford {ECO:0000312|EMBL:AAI49868.1};
RC TISSUE=Hippocampus {ECO:0000312|EMBL:AAI49868.1};
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Endoribonuclease involved in various biological functions
CC such as cellular inflammatory response and immune homeostasis, glial
CC differentiation of neuroprogenitor cells, cell death of cardiomyocytes,
CC adipogenesis and angiogenesis. Functions as an endoribonuclease
CC involved in mRNA decay. Modulates the inflammatory response by
CC promoting the degradation of a set of translationally active cytokine-
CC induced inflammation-related mRNAs, such as IL6 and IL12B, during the
CC early phase of inflammation. Prevents aberrant T-cell-mediated immune
CC reaction by degradation of multiple mRNAs controlling T-cell
CC activation, such as those encoding cytokines (IL6 and IL2), cell
CC surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor
CC (REL). Inhibits cooperatively with ZC3H12A the differentiation of
CC helper T cells Th17 in lungs. They repress target mRNA encoding the
CC Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ.
CC The cooperation requires RNA-binding by RC3H1 and the nuclease activity
CC of ZC3H12A (By similarity). Together with RC3H1, destabilizes
CC TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in
CC its 3'UTR (By similarity). Self regulates by destabilizing its own
CC mRNA. Cleaves mRNA harboring a stem-loop (SL), often located in their
CC 3'-UTRs, during the early phase of inflammation in a helicase UPF1-
CC dependent manner (By similarity). Plays a role in the inhibition of
CC microRNAs (miRNAs) biogenesis (By similarity). Cleaves the terminal
CC loop of a set of precursor miRNAs (pre-miRNAs) important for the
CC regulation of the inflammatory response leading to their degradation,
CC and thus preventing the biosynthesis of mature miRNAs (By similarity).
CC Also plays a role in promoting angiogenesis in response to inflammatory
CC cytokines by inhibiting the production of antiangiogenic microRNAs via
CC its anti-dicer RNase activity (By similarity). Affects the overall
CC ubiquitination of cellular proteins. Positively regulates
CC deubiquitinase activity promoting the cleavage at 'Lys-48'- and 'Lys-
CC 63'-linked polyubiquitin chains on TNF receptor-associated factors
CC (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation,
CC and hence negatively regulating macrophage-mediated inflammatory
CC response and immune homeostasis (By similarity). Induces also
CC deubiquitination of the transcription factor HIF1A, probably leading to
CC its stabilization and nuclear import, thereby positively regulating the
CC expression of proangiogenic HIF1A-targeted genes. Involved in a TANK-
CC dependent negative feedback response to attenuate NF-kappaB activation
CC through the deubiquitination of IKBKG or TRAF6 in response to
CC interleukin-1-beta (IL1B) stimulation or upon DNA damage (By
CC similarity). Prevents stress granules (SGs) formation and promotes
CC macrophage apoptosis under stress conditions, including arsenite-
CC induced oxidative stress, heat shock, and energy deprivation. Plays a
CC role in the regulation of macrophage polarization; promotes IL4-induced
CC polarization of macrophages M1 into anti-inflammatory M2 state. May
CC also act as a transcription factor that regulates the expression of
CC multiple genes involved in inflammatory response, angiogenesis,
CC adipogenesis and apoptosis (By similarity). Functions as a positive
CC regulator of glial differentiation of neuroprogenitor cells through an
CC amyloid precursor protein (APP)-dependent signaling pathway (By
CC similarity). Attenuates septic myocardial contractile dysfunction in
CC response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase
CC (IKK)-mediated NF-kappa-B activation, and hence myocardial pro-
CC inflammatory cytokine production (By similarity).
CC {ECO:0000250|UniProtKB:Q5D1E7, ECO:0000250|UniProtKB:Q5D1E8}.
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q5D1E8};
CC Note=Mg(2+) is required for RNase activity.
CC {ECO:0000250|UniProtKB:Q5D1E8};
CC -!- SUBUNIT: Oligomer. Found in a deubiquitination complex with TANK, USP10
CC and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-
CC beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6
CC deubiquitination. Interacts with IKBKG; this interaction increases in
CC response to DNA damage. Interacts with TANK; this interaction increases
CC in response to DNA damage and serves as a bridge to anchor both TANK
CC and USP10 into a deubiquitinating complex. Interacts with TRAF6; this
CC interaction increases in response to DNA damage and is stimulated by
CC TANK. Interacts with USP10; this interaction increases in response to
CC DNA damage and serves as a bridge to anchor both TANK and USP10 into a
CC deubiquitinating complex. Interacts with ZC3H12D. Interacts with
CC TNRC6A. Interacts with IKBKB/IKKB (By similarity). Interacts with
CC IKBKB/IKKB. Interacts with BTRC; the interaction occurs when ZC3H12A is
CC phosphorylated in a IKBKB/IKKB-dependent manner (By similarity).
CC Interacts with IRAK1; this interaction increases the interaction
CC between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with UPF1;
CC this interaction occurs in a mRNA translationally active- and
CC termination-dependent manner and is essential for ZC3H12A-mediated
CC degradation of target mRNAs (By similarity). Associates with ribosomes
CC (By similarity). Interacts with ubiquitin (By similarity).
CC {ECO:0000250|UniProtKB:Q5D1E7, ECO:0000250|UniProtKB:Q5D1E8}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q5D1E8}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q5D1E8}. Cytoplasm, P-body
CC {ECO:0000250|UniProtKB:Q5D1E8}. Rough endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q5D1E7}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q5D1E7}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q5D1E7}. Cytoplasmic granule
CC {ECO:0000250|UniProtKB:Q5D1E7}. Note=Predominantly localized in the
CC cytoplasm. Colocalizes with GW182 on many granule-like structures,
CC probably corresponding to cytoplasmic GW bodies (GWBs), also called
CC processing bodies (P bodies). Colocalizes with calnexin on the surface
CC of the rough endoplasmic reticulum (RER) membrane and with
CC translationally active polysomes (By similarity). Colocalizes with
CC ZC3H12D in cytoplasmic mRNA processing P-body, also known as GW bodies
CC (GWBs) (By similarity). {ECO:0000250|UniProtKB:Q5D1E8}.
CC -!- DOMAIN: The C3H1-type zinc finger domain and C-terminal region are
CC necessary for pre-miRNA binding. The C-terminal region and proline-rich
CC domain are necessary for oligomerization.
CC {ECO:0000250|UniProtKB:Q5D1E8}.
CC -!- PTM: Phosphorylated by IRAK1; phosphorylation is necessary for
CC subsequent phosphorylation by the I-kappa-B-kinase (IKK) complex.
CC Phosphorylated by I-kappa-B-kinase (IKK) subunits IKBKB/IKKB and
CC CHUK/IKKA at Ser-422 and Ser-426; these phosphorylations promote
CC ubiquitin proteasome-mediated degradation of ZC3H12A and hence
CC facilitates rapid and robust production of IL-6 mRNA in response to
CC toll-like receptor (TLR) or IL-1 receptor stimuli (By similarity).
CC {ECO:0000250|UniProtKB:Q5D1E7, ECO:0000250|UniProtKB:Q5D1E8}.
CC -!- PTM: Ubiquitinated; ubiquitination is induced in response to
CC interleukin IL1 receptor stimuli in a IKBKB/IKKB and IRAK1-dependent
CC manner, leading to proteasome-mediated degradation (By similarity).
CC {ECO:0000250|UniProtKB:Q5D1E7, ECO:0000250|UniProtKB:Q5D1E8}.
CC -!- PTM: Proteolytically cleaved between Arg-95 and Arg-198 by MALT1 in
CC activated T-cells; cleavage at Arg-95 is critical for promoting ZC3H12A
CC degradation in response to T-cell receptor (TCR) stimulation, and hence
CC is necessary for prolonging the stability of a set of mRNAs controlling
CC T-cell activation and Th17 cell differentiation.
CC {ECO:0000250|UniProtKB:Q5D1E7}.
CC -!- SIMILARITY: Belongs to the ZC3H12 family. {ECO:0000305}.
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DR EMBL; BC149867; AAI49868.1; -; mRNA.
DR RefSeq; NP_001095657.1; NM_001102187.1.
DR RefSeq; XP_005204850.1; XM_005204793.3.
DR AlphaFoldDB; A6QQJ8; -.
DR SMR; A6QQJ8; -.
DR STRING; 9913.ENSBTAP00000015041; -.
DR PaxDb; A6QQJ8; -.
DR PRIDE; A6QQJ8; -.
DR Ensembl; ENSBTAT00000015041; ENSBTAP00000015041; ENSBTAG00000011316.
DR GeneID; 535344; -.
DR KEGG; bta:535344; -.
DR CTD; 80149; -.
DR VEuPathDB; HostDB:ENSBTAG00000011316; -.
DR VGNC; VGNC:37097; ZC3H12A.
DR eggNOG; KOG3777; Eukaryota.
DR GeneTree; ENSGT00940000155107; -.
DR HOGENOM; CLU_013020_2_1_1; -.
DR InParanoid; A6QQJ8; -.
DR OMA; CGIFHPH; -.
DR OrthoDB; 771251at2759; -.
DR TreeFam; TF315783; -.
DR Proteomes; UP000009136; Chromosome 3.
DR Bgee; ENSBTAG00000011316; Expressed in digestive system secreted substance and 102 other tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IBA:GO_Central.
DR GO; GO:0005856; C:cytoskeleton; ISS:UniProtKB.
DR GO; GO:0042406; C:extrinsic component of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0000932; C:P-body; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0005791; C:rough endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0030867; C:rough endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0004521; F:endoribonuclease activity; ISS:UniProtKB.
DR GO; GO:0004532; F:exoribonuclease activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0035198; F:miRNA binding; ISS:UniProtKB.
DR GO; GO:0035925; F:mRNA 3'-UTR AU-rich region binding; ISS:UniProtKB.
DR GO; GO:0003730; F:mRNA 3'-UTR binding; ISS:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0004518; F:nuclease activity; ISS:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
DR GO; GO:0035613; F:RNA stem-loop binding; ISS:UniProtKB.
DR GO; GO:0061158; P:3'-UTR-mediated mRNA destabilization; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:1990869; P:cellular response to chemokine; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:0042149; P:cellular response to glucose starvation; IEA:Ensembl.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEA:Ensembl.
DR GO; GO:1904637; P:cellular response to ionomycin; ISS:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl.
DR GO; GO:1903936; P:cellular response to sodium arsenite; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; IEA:Ensembl.
DR GO; GO:0002757; P:immune response-activating signal transduction; ISS:UniProtKB.
DR GO; GO:0010587; P:miRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0044828; P:negative regulation by host of viral genome replication; IEA:Ensembl.
DR GO; GO:0055118; P:negative regulation of cardiac muscle contraction; ISS:UniProtKB.
DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; ISS:UniProtKB.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; ISS:UniProtKB.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:1903799; P:negative regulation of miRNA maturation; ISS:UniProtKB.
DR GO; GO:0010656; P:negative regulation of muscle cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0045019; P:negative regulation of nitric oxide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:UniProtKB.
DR GO; GO:0000294; P:nuclear-transcribed mRNA catabolic process, endonucleolytic cleavage-dependent decay; IBA:GO_Central.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; IEA:Ensembl.
DR GO; GO:0010942; P:positive regulation of cell death; ISS:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IEA:Ensembl.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB.
DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IEA:Ensembl.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0010884; P:positive regulation of lipid storage; IEA:Ensembl.
DR GO; GO:2000627; P:positive regulation of miRNA catabolic process; IEA:Ensembl.
DR GO; GO:0061014; P:positive regulation of mRNA catabolic process; ISS:UniProtKB.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IEA:Ensembl.
DR GO; GO:1903003; P:positive regulation of protein deubiquitination; IEA:Ensembl.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IEA:Ensembl.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IEA:Ensembl.
DR GO; GO:0090501; P:RNA phosphodiester bond hydrolysis; ISS:UniProtKB.
DR GO; GO:0090502; P:RNA phosphodiester bond hydrolysis, endonucleolytic; ISS:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB.
DR InterPro; IPR040546; Rege-1_UBA-like.
DR InterPro; IPR040757; Regnase_1/ZC3H12_C.
DR InterPro; IPR021869; RNase_Zc3h12_NYN.
DR InterPro; IPR000571; Znf_CCCH.
DR Pfam; PF18561; Regnase_1_C; 1.
DR Pfam; PF11977; RNase_Zc3h12a; 1.
DR Pfam; PF18039; UBA_6; 1.
DR PROSITE; PS50103; ZF_C3H1; 1.
PE 2: Evidence at transcript level;
KW Angiogenesis; Apoptosis; Cytoplasm; Developmental protein; Differentiation;
KW Endonuclease; Endoplasmic reticulum; Hydrolase; Magnesium; Membrane;
KW Metal-binding; Nuclease; Nucleus; Phosphoprotein; Reference proteome;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..583
FT /note="Ribonuclease ZC3H12A"
FT /id="PRO_0000341511"
FT DOMAIN 119..274
FT /note="RNase NYN"
FT /evidence="ECO:0000255"
FT ZN_FING 284..309
FT /note="C3H1-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00723"
FT REGION 1..29
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 26..71
FT /note="Ubiquitin association domain"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E7"
FT REGION 65..134
FT /note="Necessary for interaction with TANK"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E8"
FT REGION 73..119
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 96..281
FT /note="RNase"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E8"
FT REGION 198..204
FT /note="RNA binding"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E8"
FT REGION 262..290
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 285..441
FT /note="Necessary for interaction with ZC3H12D"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E8"
FT REGION 323..404
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 503..530
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 272..290
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 339..354
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 385..404
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 210
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E8"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E8"
FT MOD_RES 422
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E7"
FT MOD_RES 426
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5D1E7"
SQ SEQUENCE 583 AA; 64263 MW; A9258510092CD5D3 CRC64;
MSLWELEDRR SCQGTPRPAQ EPTAEEATTA ELQMKVDFFR KLGYSSAEIH SVLQKLGIQA
DTNTVLGELV KHGSAAERER QASPDPCPQL PLVPRGGGTP KAPTVETYPP EEDKEGSDLR
PIVIDGSNVA MSHGNKDVFS CRGILLAVNW FLERGHTDIT VFVPSWRKEQ PRPDVPITDQ
HILRDLEKKK ILVFTPSRRV GGKRVVCYDD RFIVKLAFES DGIVVSNDTY RDLQGERQEW
KRFIEERLLM YSFVNDKFMP PDDPLGRHGP SLDNFLRKKP LTSEHKKQPC PYGRKCTYGI
KCRFLHPERP SRPQRSVADE LRANALLPPS RAASKDKNSR RPSPSSQPGS LPTEHEQCSP
DRKKLGAQAS PGTPREGLMQ TFAPTGRSLP PSGSSGGSFG PSEWFPQTLD SLPYASQDCL
DSGIGSLESQ MSELWGVRGG GPGEPGPPRG PYAGYCTYGA ELPATPAFSA FSRALGAGHF
SVPADYAPPP AAFPPREYWS EPYQLPPPTQ RLQEPQAPGP GADRGPWGGA GRLAKERASV
YTKLCGVFPP HLVEAVMSRF PQLLDPQQLA AEILSYKSQH LSE
