NXN

What is NXN Protein?

NXN protein, belonging to the thioredoxin superfamily, is a redox enzyme known for catalyzing disulfide bond formation and isomerization. It plays a key role in modulating the Wnt signaling pathway by altering the oxidation state of certain proteins, thus influencing cell growth and differentiation. NXN also interacts with DVL proteins, possibly preventing DVL3 ubiquitination by the BCR(KLHL12) complex, which affects Wnt signaling. Moreover, NXN might regulate protein phosphatase 2A (PP2A) activity and control reactive oxygen species (ROS) through redox-sensitive pathways in various pathological contexts. Therefore, NXN is crucial for maintaining cellular redox balance and regulating essential cellular processes.

What is the Function of NXN Protein?

NXN is a redox enzyme involved in regulating the Wnt/β-catenin signaling pathway, affecting cell growth and differentiation. It interacts with DVL proteins to potentially prevent ubiquitination of DVL3, thus maintaining Wnt signaling balance. NXN also plays a role in redox regulation by targeting reactive oxygen species (ROS), maintaining cellular redox stability, and may act as a transcription regulator impacting PP2A and Akt pathways. Additionally, NXN interacts with the TLR4/MYD88 pathway to modulate NF-κB nuclear translocation, influencing innate immunity and inflammation. As an antioxidant enzyme, NXN protects against oxidative stress, participating crucially in cellular physiology and pathology by managing various redox-sensitive signaling pathways.

NXN Related Signaling Pathway

Nucleoredoxin (NXN) is a pivotal redox regulator that influences various cellular processes. It interacts with the WNT/β-catenin pathway, impacting cell growth and differentiation, and plays a role in the TLR4/MYD88 signaling pathway, affecting immune responses. NXN also engages with proteins like SEC63, PFK1, FLII, and CAMK2A, which are involved in cell cycle progression and cytoskeletal dynamics. Through these interactions, NXN helps maintain redox balance and immune function, crucial for cell development, differentiation, and metabolism. Its activity is essential for balancing the cellular internal environment and responding to external signals, making it a key player in both physiological and pathological contexts.

NXN Related Diseases

Nucleoredoxin (NXN) is a protein that’s crucial for maintaining cellular redox balance, playing a part in several signaling pathways such as WNT/β-catenin. This protein is linked with various diseases, including Robinow syndrome through genetic connections, and it influences cancer progression like liver and colon cancer. NXN also plays a role in managing oxidative stress-related disorders such as alcoholic liver disease and diabetes, impacting liver function and fat formation. In Alzheimer’s, NXN is involved in neuronal dysfunction and immune response, while it contributes to retinal degeneration like retinitis pigmentosa and affects obesity by influencing fat cell differentiation. Its involvement in such diverse conditions highlights NXN as a promising target for therapeutic interventions.

Bioapplications of NXN

Recombinant NXN protein is widely used in research, industry, and medical studies. In research, it’s studied for its role in regulating the Wnt/β-catenin signaling pathway, impacting cell growth and differentiation as well as redox reactions. In industrial applications, recombinant NXN protein helps produce specific antibodies used in various assays like Western Blot and ELISA. Medically, NXN is linked to diseases such as cervical squamous cell carcinoma, where changes in its expression can serve as diagnostic markers. Additionally, recombinant NXN can be part of therapeutic strategies, like enhancing treatments for cervical carcinoma by overexpressing NXN or using its vectors. Overall, recombinant NXN protein plays a critical role in advancing scientific research, diagnostics, and therapy development.

Case Study 1: Zhang Y. et al. Cell Death Dis. 2022

The grim outlook for hepatocellular carcinoma (HCC) is often due to its tendency to spread quickly. In this context, the nucleoredoxin (NXN) protein seems to play a suppressive role. Studies show NXN levels are lower in HCC tissues compared to normal liver tissues, and lower NXN is linked to worse survival rates. Experimentally, boosting NXN reduces the growth and spread of HCC cells by curbing the epithelial-mesenchymal transition (EMT). NXN achieves this by promoting the degradation of Snail protein, thanks to its interaction with DUB3. In essence, NXN limits HCC progression by targeting Snail for breakdown.

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  Fig1. The efficiency of NXN overexpression and knockdown was measured by Western blot assays.
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  Fig2. NXN overexpression enhanced ubiquitination of Snail in 293 T, PLC-8024 and Huh7 cells.

Case Study 2: Valek L. et al. Antioxidants (Basel). 2021

Nucleoredoxin (NXN) impacts WNT signaling by regulating Disheveled proteins, and its deficiency in mice points to issues in cell fate decisions, like abnormal skull and organ development. When NXN was knocked down in SH-SY5Y neuroblastoma cells, these cells didn’t show different survival rates under redox stress but did proliferate more, showing an increased mitotic rate. These NXN-deficient cells also had elevated basic respiration and expressed more redox-sensitive proteins like Hsc70 and HSP90. They showed increased autophagy during stress, suggesting that enhanced self-renewal and autophagy, along with stress protein expression, could potentially be beneficial for neuron longevity, given that SH-SY5Y cells model neurons.

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  Fig3. Exemplary Western Blot and quantification of NXN.
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  Fig4. Immunofluorescence analysis of LC3b (LC3-I and LC3b-II) in naïve scrNXN and shNXN SH-Sy5Y cells.

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  Fig1. Schematic illustration depicting the role of NXN in suppressing tumor metastasis through promoting degradation of Snail. (Yuanping Zhang, 2022)
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  Fig2. Schematic representation of NXN-regulated signaling pathways. (Osiris Germán Idelfonso-García, 2022)

NXN has several biochemical functions, for example, protein-disulfide reductase activity,thioredoxin-disulfide reductase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by NXN itself. We selected most functions NXN had, and list some proteins which have the same functions with NXN. You can find most of the proteins on our site.

Function	Related Protein
thioredoxin-disulfide reductase activity	TXNRD1,TXNRD3,TXNRD2,TRR1

NXN has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with NXN here. Most of them are supplied by our site. Hope this information will be useful for your research of NXN.

USP3;SEC63