Tnip2-KO Mouse

TNIP2, also known as ABIN2, is a protein that functions as a negative regulator of NF-κB signaling. It binds to A20 to suppress inflammatory cytokines-induced NF-κB activation, thus inhibiting inflammatory response and apoptosis. It is also involved in RNA metabolism. The NF-κB signaling pathway is pivotal in controlling cellular responses to environmental stresses, and TNIP2's role in this pathway is crucial for maintaining normal cellular function [1,5,6].

In various disease conditions, TNIP2 has been shown to play significant roles. In Alzheimer's disease (AD) cell and mouse models, TNIP2 protein level declined significantly. Overexpression of TNIP2 decreased β-secretase (BACE1) and C99 protein levels, as well as Aβ peptides, by promoting BACE1 mRNA degradation through binding to its 3' untranslated region, effectively inhibiting amyloidogenic processing [1]. In major depressive disorder (MDD), TNIP2 mRNA expression was higher in monocytes from patients, positively correlated with GRβ expression and depression severity. GRβ overexpression promoted TNIP2 and TNF-α mRNA levels, and TNIP2 was required for GRβ-mediated TNF-α increase, suggesting the GRβ/TNIP2/TNF-α axis may induce inflammation in MDD [2]. In rheumatoid arthritis (RA), multi-ancestry genome-wide association analyses identified TNIP2 as a candidate gene, suggesting its role in the disease's etiology [3]. In pulmonary arterial hypertension (PAH), a novel missense variant in TNIP2 was discovered in affected individuals. TNIP2 knockdown increased NF-κB activity and cell proliferation in healthy lung pericytes, indicating its role in pulmonary vascular remodeling [4]. In spinal cord injury (SCI) rat models, TNIP2 expression increased, and its overexpression inhibited M1 polarization and pro-inflammatory cytokine production in microglia, protecting against inflammatory responses [5]. In bronchopulmonary dysplasia (BPD), TNIP2, as a direct target of miR34a, negatively regulated the activation of NLRP3 inflammasome and production of IL-1β. Overexpressing TNIP2 ameliorated hyperoxia-induced IL-1β production and cell apoptosis, suggesting it may be a potential clinical marker for BPD [7]. In multiple organ dysfunction syndrome (MODS) following severe trauma, TNIP2 was decreased in patients and MODS rats. TNIP2-plasmid administration inhibited the increase in inflammatory and oxidative stress-related markers and NF-κB activation in MODS rats, indicating its protective role [8]. In osteoarthritis (OA), NAV2-AS5 relieved chondrocyte inflammation by targeting miR-8082/TNIP2, with TNIP2 downregulated in OA patients [9].

In conclusion, TNIP2 is a key regulator in the NF-κB signaling pathway and RNA metabolism. Through studies using various disease models such as those for AD, MDD, RA, PAH, SCI, BPD, MODS, and OA, TNIP2 has been shown to play important roles in inflammation, apoptosis, and disease-related processes. These model-based studies help in understanding the biological functions of TNIP2 and provide potential therapeutic targets for these diseases.

References:

1. Chen, Long, Wang, Lu, Zhou, Gui-Feng, Yang, Jie, Chen, Guo-Jun. 2023. TNIP2 inhibits amyloidogenesis by regulating the 3'UTR of BACE1: An in vitro study. In Neuroscience letters, 808, 137265. doi:10.1016/j.neulet.2023.137265. https://pubmed.ncbi.nlm.nih.gov/37085111/

2. Chiang, Ting-I, Hung, Yi-Yung, Wu, Ming-Kung, Huang, Ya-Ling, Kang, Hong-Yo. 2021. TNIP2 mediates GRβ-promoted inflammation and is associated with severity of major depressive disorder. In Brain, behavior, and immunity, 95, 454-461. doi:10.1016/j.bbi.2021.04.021. https://pubmed.ncbi.nlm.nih.gov/33932528/

3. Ishigaki, Kazuyoshi, Sakaue, Saori, Terao, Chikashi, Okada, Yukinori, Raychaudhuri, Soumya. 2022. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. In Nature genetics, 54, 1640-1651. doi:10.1038/s41588-022-01213-w. https://pubmed.ncbi.nlm.nih.gov/36333501/

4. Pienkos, Shaun, Gallego, Natalia, Condon, David F, Tenorio-Castaño, Jair, de Jesús Pérez, Vinicio A. 2021. Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension. In Frontiers in medicine, 8, 625763. doi:10.3389/fmed.2021.625763. https://pubmed.ncbi.nlm.nih.gov/33996849/

5. Fu, Jiawei, Wu, Chunshuai, Xu, Guanhua, Ji, Chunyan, Cui, Zhiming. 2023. Protective effect of TNIP2 on the inflammatory response of microglia after spinal cord injury in rats. In Neuropeptides, 101, 102351. doi:10.1016/j.npep.2023.102351. https://pubmed.ncbi.nlm.nih.gov/37329819/

6. Banks, Charles A S, Boanca, Gina, Lee, Zachary T, Florens, Laurence, Washburn, Michael P. 2016. TNIP2 is a Hub Protein in the NF-κB Network with Both Protein and RNA Mediated Interactions. In Molecular & cellular proteomics : MCP, 15, 3435-3449. doi:. https://pubmed.ncbi.nlm.nih.gov/27609421/

7. Tao, Xuwei, Mo, Luxia, Zeng, Lingkong. 2022. Hyperoxia Induced Bronchopulmonary Dysplasia-Like Inflammation via miR34a-TNIP2-IL-1β Pathway. In Frontiers in pediatrics, 10, 805860. doi:10.3389/fped.2022.805860. https://pubmed.ncbi.nlm.nih.gov/35433535/

8. Gong, Hui, Sheng, Xiaomin, Xue, Jianhua, Zhu, Dongbo. 2019. Expression and role of TNIP2 in multiple organ dysfunction syndrome following severe trauma. In Molecular medicine reports, 19, 2906-2912. doi:10.3892/mmr.2019.9893. https://pubmed.ncbi.nlm.nih.gov/30720079/

9. Wang, Pu, Wang, Yuhao, Ma, Baoan. 2022. Long noncoding RNA NAV2-AS5 relieves chondrocyte inflammation by targeting miR-8082/TNIP2 in osteoarthritis. In Cell cycle (Georgetown, Tex.), 22, 796-807. doi:10.1080/15384101.2022.2154554. https://pubmed.ncbi.nlm.nih.gov/36503346/