Zc3h12c, also known as Regnase-3, is an important member of the CCCH-zinc finger protein family. It functions as a post-transcriptional regulator, mainly involved in host immune and inflammatory responses. It has been associated with pathways such as NF-κB activation regulation, and plays a crucial role in maintaining immune and inflammatory homeostasis. Genetic models, like Zc3h12c-deficient mice, have been valuable in studying its functions [1,2,3,5].

Zc3h12c-deficient mice develop hypertrophic lymph nodes, indicating its role in preventing lymphadenopathy of skin-draining lymph nodes, likely through regulating Tnf mRNA stability in dendritic cells [1]. In macrophages, loss of Gfi1 upregulates Zc3h12c, which in turn inhibits NF-κB activation, forming a negative feedback loop [2]. In endothelial cells, knockdown of Zc3h12c increases TNFα-induced expression of chemokines and adhesive molecules, suggesting it inhibits vascular inflammation by suppressing the NF-κB pathway [3]. Also, in macrophages, overexpression of Zc3h12c mitigates the release of TNF-α and IL-6 triggered by lipopolysaccharide, while its depletion increases cytokine production [5]. Additionally, Regnase-1/3 (Zc3h12a/c) control lymphoid-myeloid lineage bias in hematopoietic stem and progenitor cells via regulating Nfkbiz mRNA [6].

In summary, Zc3h12c is a key regulator in multiple biological processes related to the immune response and inflammation. Studies using Zc3h12c-deficient mouse models have revealed its roles in preventing lymphadenopathy, regulating NF-κB activation in macrophages and endothelial cells, modulating cytokine release in macrophages, and controlling lineage biases in hematopoietic cells. These findings contribute to understanding its significance in immune-related diseases such as psoriasis, vascular inflammation, and potentially others [1,2,3,4,5,6].

References:

1. Clayer, Elise, Frank, Daniel, Anderton, Holly, Chopin, Michaël, Bouillet, Philippe. 2022. ZC3H12C expression in dendritic cells is necessary to prevent lymphadenopathy of skin-draining lymph nodes. In Immunology and cell biology, 100, 160-173. doi:10.1111/imcb.12521. https://pubmed.ncbi.nlm.nih.gov/35048402/

2. Guo, Guo, Fu, Rui, Zhang, Lichen, Liang, Yinming, Zheng, Qianqian. 2020. Gfi1 and Zc3h12c orchestrate a negative feedback loop that inhibits NF-kB activation during inflammation in macrophages. In Molecular immunology, 128, 219-226. doi:10.1016/j.molimm.2020.10.023. https://pubmed.ncbi.nlm.nih.gov/33157351/

3. Liu, Ling, Zhou, Zhou, Huang, Shengping, Fu, Mingui, Chen, Y Eugene. . Zc3h12c inhibits vascular inflammation by repressing NF-κB activation and pro-inflammatory gene expression in endothelial cells. In The Biochemical journal, 451, 55-60. doi:10.1042/BJ20130019. https://pubmed.ncbi.nlm.nih.gov/23360436/

4. Wawro, Mateusz, Kochan, Jakub, Sowinska, Weronika, Cichy, Joanna, Kasza, Aneta. 2021. Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology. In International journal of molecular sciences, 22, . doi:10.3390/ijms22147311. https://pubmed.ncbi.nlm.nih.gov/34298932/

5. Zhao, Yinxia, Zhu, Maoli, Wu, Songfang, Zhou, Ying, Li, Shuijun. 2024. Unlocking the power of Zc3h12c: Orchestrating Macrophage activation and elevating the innate immune response. In Cellular immunology, 401-402, 104837. doi:10.1016/j.cellimm.2024.104837. https://pubmed.ncbi.nlm.nih.gov/38810592/

6. Uehata, Takuya, Yamada, Shinnosuke, Ori, Daisuke, Miyazaki, Masaki, Takeuchi, Osamu. . Regulation of lymphoid-myeloid lineage bias through regnase-1/3-mediated control of Nfkbiz. In Blood, 143, 243-257. doi:10.1182/blood.2023020903. https://pubmed.ncbi.nlm.nih.gov/37922454/