Alternative titles; symbols
HGNC Approved Gene Symbol: ZC3H12A
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:37,474,580-37,484,377 (from NCBI)
ZC3H12A is a CCCH-type zinc finger protein, like TTP (ZFP36; 190700), ZAP (ZC3HAV1; 607312), and ROQUIN (RC3H1; 609424), whereas most mammalian zinc finger proteins are CCHH- or CCCC-type proteins. The ZC3H12A gene encodes an essential RNase that controls the stability of a set of inflammatory genes (Matsushita et al., 2009). Liang et al. (2008) found that ZC3H12A, also known as MCPIP1, and other other MCPIP proteins, MCPIP2 (ZC3H12B; 300889), MCPIP3 (ZC3H12C; 615001), and MCPIP4 (ZC3H12D; 611106), regulate macrophage activation.
Using gene array analysis to identify MCP1 (158105)-induced genes in human monocytes, followed by database analysis and RT-PCR of peripheral blood monocyte RNA, Zhou et al. (2006) cloned ZC3H12A, which they called MCPIP. The deduced 599-amino acid protein has a calculated molecular mass of 65.8 kD and contains 2 proline-rich potential activation domains, a monopartite nuclear localization sequence, and a zinc finger motif. ZC3H12A shares 82% amino acid identity with the mouse ortholog. Northern blot analysis detected a 1.8-kb transcript in MCP1-treated monocytes, and fluorescence microscopy showed ZC3H12A expressed in HEK293 cells as localized to the nucleus.
By TUNEL assay and immunoblot analysis of ZC3H12A-transfected HEK293 and cardiomyoblast cells, Zhou et al. (2006) showed that ZC3H12A expression caused caspase-3 (600636) activation and apoptosis. In vitro, ZC3H12A transactivated transcription from a luciferase reporter and induced expression of many apoptotic genes, including BFAR (619516), TNFR2 (191191), LTBR (600979), and TNFRSF10C (603613). The zinc finger domain of ZC3H12A was required for apoptosis as well as for transactivation. Zhou et al. (2006) concluded that ZC3H12A induction of apoptosis is mediated by transcriptional activation of genes that play a role in cell death. Using real-time PCR analysis of heart tissue from patients with ischemic and nonischemic heart disease, Zhou et al. (2006) showed increased ZC3H12A expression in samples from ischemic heart disease patients.
Liang et al. (2008) showed that mouse macrophages treated with lipopolysaccharide (LPS), but not Ifng (147570), showed high induction of MCPIP1 by Northern blot analysis. TNF (191160) or IL1B (147720) also induced expression of MCPIP1 in a human monocyte cell line. Western blot analysis detected expression of 66.5-kD MCPIP1 protein by mouse or human macrophages or monocytes stimulated with LPS. Cells overexpressing MCPIP1 showed markedly reduced expression of TNF, IL6 (147620), MCP1, and nitric oxide but had no effect on LDL uptake. Cytokine expression induction in response to LPS was enhanced by MCPIP1 siRNA treatment. Liang et al. (2008) proposed that regulation of cytokine expression by MCPIP1 appears to occur by an indirect mechanism, possibly involving feedback inhibition of LPS-induced NFKB (see 164011) signaling.
Lin et al. (2014) noted that MCPIP1, as an RNase, targets viral RNA and has antiviral activity. They found that infection of a hepatoma cell line with hepatitis C virus (HCV; see 609532) induced MCPIP1 expression. Expression of MCPIP1 was higher in liver tissue from patients with chronic HCV infection compared with those without chronic infection. Knockdown of MCPIP1 expression enhanced HCV replication and HCV-mediated expression of proinflammatory cytokines, such as TNF, IL6, and MCP1. In contrast, overexpression of MCPIP1 significantly inhibited HCV replication and proinflammatory cytokine expression. Mutation analysis indicated that disruption of the RNA-binding and oligomerization abilities, as well as the RNase activity, of MCPIP1, but not the deubiquitinase activity, impaired its inhibitory activity against HCV replication. Immunocytochemical analysis demonstrated MCPIP1 colocalization with HCV RNA. A replication-defective HCV mutant was susceptible to MCPIP1-mediated RNA degradation. Lin et al. (2014) proposed that MCPIP1 suppresses HCV replication and HCV-induced proinflammatory responses.
Regnase-1 and roquin are RNA-binding proteins essential for degradation of inflammation-related mRNAs. Using HeLa cells and other mammalian cells, Mino et al. (2015) found that, although regnase-1 and roquin regulated an overlapping set of mRNAs through a common stem-loop structure, they functioned in distinct subcellular locations, with regnase-1 functioning in ribosome/endoplasmic reticulum, and roquin functioning in processing body/stress granules. Regnase-1 cleaved and degraded translationally active RNAs in a UPF1 (601430) helicase-dependent manner, whereas roquin acted on translationally inactive mRNAs, independent of UPF1. Deficiency of both regnase-1 and roquin led to large increases in their target mRNAs. Mino et al. (2015) concluded that these RNA-binding proteins control inflammation in spatiotemporally distinct manners, with regnase-1 controlling the early phase of inflammation, when mRNAs are more actively translated, and roquin controlling late phases of inflammation.
Wei et al. (2019) used an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence, and robust effector function in tumors. REGNASE-1-deficient CD8+ T cells showed markedly improved therapeutic efficacy against mouse models of melanoma and leukemia. By using a secondary genome-scale CRISPR-Cas9 screening, Wei et al. (2019) identified BATF (612476) as the key target of REGNASE-1 and as a rheostat that shapes antitumor responses. Loss of BATF suppressed the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8+ T cells. By contrast, the targeting of additional signaling factors, including PTPN2 (176887) and SOCS1 (603597), improved the therapeutic efficacy of REGNASE-1-deficient CD8+ T cells. Wei et al. (2019) concluded that their findings suggested that T-cell persistence and effector function can be coordinated in tumor immunity.
Zhou et al. (2006) determined that the ZC3H12A gene contains 5 exons and spans 8.9 kb.
By genomic sequence analysis, Zhou et al. (2006) mapped the ZC3H12A gene to chromosome 1p35.3-p33.
Zhou et al. (2006) used transgenic mice expressing MCP1 in cardiomyocytes as a model of heart failure following cardiac inflammation and found that these mice had increased ZC3H12A expression, increased cell death, and accumulation of ZC3H12A protein in myocardial vacuoles, characteristic of both human and mouse heart failure.
Matsushita et al. (2009) identified the Toll-like receptor (TLR)-inducible gene ZC3H12A as an immune response modifier that has an essential role in preventing immune disorders. Zc3h12a-deficient mice suffered from severe anemia, and most died within 12 weeks. Null mice also showed augmented serum immunoglobulin levels and autoantibody production, together with a greatly increased number of plasma cells, as well as infiltration of plasma cells to the lung. Most Zc3h12a-null splenic T cells showed effector/memory characteristics and produced interferon-gamma (147570) in response to T-cell receptor stimulation. Macrophages from Zc3h12a-null mice showed highly increased production of interleukin-6 (IL6; 147620) and IL-12p40 (IL12B; 161561), but not TNF (191160), in response to TLR ligands. Although the activation of TLR signaling pathways was normal, Il6 mRNA decay was severely impaired in the Zc3h12a-null macrophages. Overexpression of Zc3h12a accelerated Il6 mRNA degradation via its 3-prime untranslated region (UTR), and destabilized RNAs with 3-prime UTRs for genes including Il6, Il12p40, and the calcitonin receptor gene Calcr (114131). Zc3h12a contains a putative N-terminal nuclease domain, and the expressed protein had RNase activity, consistent with a role in the decay of Il6 mRNA. Matsushita et al. (2009) concluded that Zc3h12a is an essential RNase that prevents immune disorders by directly controlling the stability of a set of inflammatory genes.
Uehata et al. (2013) generated mice with a conditional deletion of Zc3h12a in T cells and observed T- and B-cell activation and the development of autoimmune disease. T cells adoptively transferred from mutant, but not control, mice persisted and caused splenomegaly in recipient mice. Zc3h12a-deficient T cells had enhanced proliferative responses and Ifng (147570) production. Examination of Zc3h12a-deficient T cells showed a loss of ability to cleave the 3-prime UTRs of the transcription factor Rel (164910), surface-expressed Ox40 (TNFRSF4; 600315), and the cytokine Il2 (147680). T-cell receptor stimulation of wildtype T cells resulted in cleavage of Zc3h12a at arg111 by Malt1 (604860), thus freeing T cells from Zc3h12a-mediated suppression. Malt1 activity was also critical for the stability of Rel, Ox40, and Il2 mRNAs. Uehata et al. (2013) concluded that dynamic control of ZC3H12A activity is critical for controlling T-cell activation.
Liang, J., Wang, J., Azfer, A., Song, W., Tromp, G., Kolattukudy, P. E., Fu, M. A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. J. Biol. Chem. 283: 6337-6346, 2008. [PubMed: 18178554] [Full Text: https://doi.org/10.1074/jbc.M707861200]
Lin, R.-J., Chu, J.-S., Chien, H.-L., Tseng, C.-H., Ko, P.-C., Mei, Y.-Y., Tang, W.-C., Kao, Y.-T., Cheng, H.-Y., Liang, Y.-C., Lin, S.-Y. MCPIP1 suppresses hepatitis C virus replication and negatively regulates virus-induced proinflammatory cytokine responses. J. Immun. 193: 4159-4168, 2014. [PubMed: 25225661] [Full Text: https://doi.org/10.4049/jimmunol.1400337]
Matsushita, K., Takeuchi, O., Standley, D. M., Kumagai, Y., Kawagoe, T., Miyake, T., Satoh, T., Kato, H., Tsujimura, T., Nakamura, H., Akira, S. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458: 1185-1190, 2009. [PubMed: 19322177] [Full Text: https://doi.org/10.1038/nature07924]
Mino, T., Murakawa, Y., Fukao, A., Vandenbon, A., Wessels, H.-H., Ori, D., Uehata, T., Tartey, S., Akira, S., Suzuki, Y., Vinuesa, C. G., Ohler, U., Standley, D. M., Landthaler, M., Fujiwara, T., Takeuchi, O. Regnase-1 and Roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell 161: 1058-1073, 2015. [PubMed: 26000482] [Full Text: https://doi.org/10.1016/j.cell.2015.04.029]
Uehata, T., Iwasaki, H., Vandenbon, A., Matsushita, K., Hernandez-Cuellar, E., Kuniyoshi, K., Satoh, T., Mino, T., Suzuki, Y., Standley, D. M., Tsujimura, T., Rakugi, H., Isaka, Y., Takeuchi, O., Akira, S. Malt1-induced cleavage of Regnase-1 in CD4+ helper T cells regulates immune activation. Cell 153: 1036-1049, 2013. [PubMed: 23706741] [Full Text: https://doi.org/10.1016/j.cell.2013.04.034]
Wei, J., Long, L., Zheng, W., Dhungana, Y., Lim, S. A., Guy, C., Wang, Y., Wang, Y.-D., Qian, C., Xu, B., Kc, A., Saravia, J., Huang, H., Yu, J., Doench, J. G., Geiger, T. L., Chi, H. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576: 471-476, 2019. [PubMed: 31827283] [Full Text: https://doi.org/10.1038/s41586-019-1821-z]
Zhou, L., Azfer, A., Niu, J., Graham, S., Choudhury, M., Adamski, F. M., Younce, C., Binkley, P. F., Kolattukudy, P. E. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ. Res. 98: 1177-1185, 2006. [PubMed: 16574901] [Full Text: https://doi.org/10.1161/01.RES.0000220106.64661.71]