ZC3H12A

ZC3H12A is an MCP1 (CCL2; MIM 158105)-induced protein that acts as a transcriptional activator and causes cell death of cardiomyocytes, possibly via induction of genes associated with apoptosis.

ZINC FINGER CCCH-TYPE CONTAINING 12A

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).
Also plays 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).
(Microbial infection) Binds to Japanese encephalitis virus (JEV) and Dengue virus (DEN) RNAs.
(Microbial infection) Exhibits antiviral activity against HIV-1 in lymphocytes by decreasing the abundance of HIV-1 viral RNA species.

Biological Process 3'-UTR-mediated mRNA destabilization Source:UniProtKB1 Publication
Biological Process angiogenesis Source:UniProtKB-KW
Biological Process apoptotic process Source:UniProtKB-KW
Biological Process cell differentiation Source:UniProtKB-KW
Biological Process cellular response to chemokine Source:UniProtKB2 Publications
Biological Process cellular response to DNA damage stimulus Source:UniProtKB1 Publication
Biological Process cellular response to glucose starvation Source:UniProtKB
Biological Process cellular response to interleukin-1 Source:UniProtKB
Biological Process cellular response to ionomycin Source:UniProtKB
Biological Process cellular response to lipopolysaccharide Source:UniProtKB2 Publications
Biological Process cellular response to oxidative stress Source:UniProtKB
Biological Process cellular response to sodium arsenite Source:UniProtKB
Biological Process cellular response to tumor necrosis factor Source:UniProtKB1 Publication
Biological Process cellular response to virus Source:UniProtKB1 Publication
Biological Process defense response to virus Source:UniProtKB-KW
Biological Process immune response-activating signaling pathway Source:UniProtKB1 Publication
Biological Process inflammatory response Source:UniProtKB-KW
Biological Process miRNA catabolic process Source:UniProtKB1 Publication
Biological Process negative regulation by host of viral genome replication Source:UniProtKB1 Publication
Biological Process negative regulation of cardiac muscle contraction Source:UniProtKB
Biological Process negative regulation of cytokine production involved in inflammatory response Source:UniProtKB
Biological Process negative regulation of gene expression Source:BHF-UCL1 Publication
Biological Process negative regulation of I-kappaB kinase/NF-kappaB signaling Source:UniProtKB1 Publication
Biological Process negative regulation of interleukin-1 beta production Source:UniProtKB
Biological Process negative regulation of interleukin-6 production Source:BHF-UCL1 Publication
Biological Process negative regulation of macrophage activation Source:BHF-UCL1 Publication
Biological Process negative regulation of muscle cell apoptotic process Source:UniProtKB
Biological Process negative regulation of NF-kappaB transcription factor activity Source:BHF-UCL1 Publication
Biological Process negative regulation of NIK/NF-kappaB signaling Source:UniProtKB
Biological Process negative regulation of nitric oxide biosynthetic process Source:BHF-UCL1 Publication
Biological Process negative regulation of protein phosphorylation Source:UniProtKB
Biological Process negative regulation of T-helper 17 cell differentiation Source:UniProtKB
Biological Process negative regulation of tumor necrosis factor production Source:BHF-UCL1 Publication
Biological Process negative regulation of type II interferon production Source:UniProtKB
Biological Process nervous system development Source:UniProtKB-KW
Biological Process nuclear-transcribed mRNA catabolic process, endonucleolytic cleavage-dependent decay Source:UniProtKB
Biological Process positive regulation of angiogenesis Source:UniProtKB1 Publication
Biological Process positive regulation of autophagy Source:BHF-UCL1 Publication
Biological Process positive regulation of cell death Source:UniProtKB1 Publication
Biological Process positive regulation of defense response to virus by host Source:UniProtKB1 Publication
Biological Process positive regulation of endothelial cell migration Source:UniProtKB1 Publication
Biological Process positive regulation of execution phase of apoptosis Source:UniProtKB
Biological Process positive regulation of fat cell differentiation Source:BHF-UCL1 Publication
Biological Process positive regulation of gene expression Source:BHF-UCL1 Publication
Biological Process positive regulation of lipid storage Source:BHF-UCL1 Publication
Biological Process positive regulation of miRNA catabolic process Source:UniProtKB1 Publication
Biological Process positive regulation of mRNA catabolic process Source:UniProtKB1 Publication
Biological Process positive regulation of p38MAPK cascade Source:UniProtKB1 Publication
Biological Process positive regulation of protein deubiquitination Source:UniProtKB1 Publication
Biological Process positive regulation of protein import into nucleus Source:UniProtKB1 Publication
Biological Process positive regulation of reactive oxygen species metabolic process Source:BHF-UCL1 Publication
Biological Process positive regulation of transcription by RNA polymerase II Source:UniProtKB2 Publications
Biological Process protein complex oligomerization Source:UniProtKB2 Publications
Biological Process protein deubiquitination Source:UniProtKB1 Publication
Biological Process regulation of gene expression Source:UniProtKB1 Publication
Biological Process RNA phosphodiester bond hydrolysis Source:UniProtKB
Biological Process RNA phosphodiester bond hydrolysis, endonucleolytic Source:GO_Central1 Publication
Biological Process T cell receptor signaling pathway Source:UniProtKB

Nucleus
Cytoplasm
Cytoplasm, P-body
Rough endoplasmic reticulum membrane
Cytoplasmic granule
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 (By similarity).
Colocalizes with ZC3H12D in cytoplasmic mRNA processing P-body, also known as GW bodies (GWBs) (PubMed:22055188, PubMed:26134560).

Increased expression of ZC3H12A is associated with ischemic heart disease (PubMed:16574901).

Phosphorylated by IRAK1; phosphorylation is necessary for subsequent phosphorylation by the I-kappa-B-kinase (IKK) complex. Phosphorylated by I-kappa-B-kinase (IKK) subunits IKBKB/IKKB and CHUK/IKKA at Ser-438 and Ser-442; these phosphorylations promote ubiquitin proteasome-mediated degradation of ZC3H12A and hence facilitates rapid and robust production of IL-6 mRNA in response to toll-like receptor (TLR) or IL-1 receptor stimuli (By similarity).
(Microbial infection) Rapidly degraded in activated T-cells in response to phorbol 13-acetate 12-myristate (PMA) during HIV-1 viral infection (PubMed:24191027).
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).
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.