Recombinant Mouse Endoribonuclease ZC3H12A (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:26000482). 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:19322177, PubMed:21115689, PubMed:23185455, PubMed:26000482). 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) (PubMed:19322177, PubMed:21115689, PubMed:23185455, PubMed:23706741, PubMed:26000482). 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 (PubMed:25282160). Together with RC3H1, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (PubMed:29244194, PubMed:35819231). Self regulates by destabilizing its own mRNA (PubMed:22037600). 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:19322177, PubMed:23185455, PubMed:23706741, PubMed:26000482, PubMed:26134560). 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). 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 (By similarity). Affects the overall ubiquitination of cellular proteins (PubMed:21115689). 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 (PubMed:21115689). 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 (PubMed:21971051). Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state (PubMed:25934862). May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (PubMed:18178554, PubMed:19666473, PubMed:22739135). 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 pro-inflammatory cytokine production (PubMed:21616078)

Subcellular Location

Nucleus; Cytoplasm; Rough endoplasmic reticulum membrane (Peripheral membrane protein); Cytoplasmic granule; Cytoplasm, P-body

Disease Association

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

Tissue Specificity

Expressed in CD4(+) helper T-cells (at protein level) (PubMed:29244194). Highly expressed in macrophages (PubMed:18178554). Expressed in lung, lymph nodes, spleen and thymus (PubMed:22037600). Expressed weakly in heart (PubMed:21616078). Expressed weakly in cardiomyocytes (at protein level) (PubMed:16574901). Expressed in spleen, lung, intestine, brown adipose tissue and thymus (PubMed:18682727). Weakly expressed in the heart (PubMed:16574901). Weakly expressed in cardiomyocytes (PubMed:16574901)

Subunit

Oligomer (By similarity). 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 (By similarity). Interacts with IKBKB/IKKB (PubMed:22037600). Interacts with BTRC; the interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner (PubMed:22037600). Interacts with IRAK1; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (PubMed:22037600). 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 (PubMed:26000482). Associates with ribosomes (PubMed:26000482). Interacts with ubiquitin (PubMed:21115689)

• Zhou L. et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. — Circ. Res. (2006)
• Carninci P. et al. The transcriptional landscape of the mammalian genome. — Science (2005)
• Church D.M. et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. — PLoS Biol. (2009)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Liang J. et al. A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. — J. Biol. Chem. (2008)
• Liang J. et al. Genome-wide survey and expression profiling of CCCH-zinc finger family reveals a functional module in macrophage activation. — PLoS ONE (2008)
• Younce C.W. et al. MCP-1 (monocyte chemotactic protein-1)-induced protein, a recently identified zinc finger protein, induces adipogenesis in 3T3-L1 pre-adipocytes without peroxisome proliferator-activated receptor gamma. — J. Biol. Chem. (2009)
• Matsushita K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. — Nature (2009)