Unc5CL, also known as ZUD, is a death domain-containing protein. It is involved in a novel MyD88-independent mode of IRAK signaling, leading to the activation of transcription factor nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase. This signaling pathway is crucial for innate and adaptive immunity. Unc5CL requires IRAK1, IRAK4, and TNF receptor-associated factor 6 for pathway activation [1].

Transcriptional profiling identified chemokines like IL-8, CXCL1, and CCL20 as Unc5CL target genes. Its prominent expression in mucosal tissues and ability to induce a pro-inflammatory program suggest its role in epithelial inflammation, immunity, and mucosal diseases such as inflammatory bowel disease [1]. Additionally, Unc5CL has been identified as a gemcitabine-resistance-related gene in bladder cancer. A prognostic model including Unc5CL was established, and patients in the high-risk group based on this model had different immune cell infiltration patterns, indicating its potential role in bladder cancer prognosis and immune microenvironment regulation [2]. In irritable bowel syndrome (IBS), Unc5CL was found in the clusters of a sub-network constructed from protein-protein interaction analysis, suggesting its potential role in the regulation of IBS [3]. Unc5CL has also been associated with esophageal cancer risk. A SNP near Unc5CL (rs10484761 at 6p21) was found to be associated with an increased risk of esophageal cancer in a Chinese Han population [4]. In a GWAS of gastric adenocarcinoma, a SNP near Unc5CL (rs2294693 at 6p21.1) was significantly associated with gastric non-cardia cancer risk [6]. Moreover, Unc5CL has been identified as a putative Alzheimer's disease risk gene through integrating genetic variation and co-expression transcriptome networks [5].

In conclusion, Unc5CL is a key protein involved in immune-related signaling pathways. Its role in various diseases such as inflammatory bowel disease, bladder cancer, esophageal cancer, gastric non-cardia cancer, and potentially Alzheimer's disease, as revealed through multiple studies, highlights its importance in understanding disease mechanisms. These findings from different research models contribute to the understanding of the biological functions of Unc5CL and provide potential targets for disease treatment and prevention.

References:

1. Heinz, L X, Rebsamen, M, Rossi, D C, Schneider, P, Tschopp, J. 2011. The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. In Cell death and differentiation, 19, 722-31. doi:10.1038/cdd.2011.147. https://pubmed.ncbi.nlm.nih.gov/22158417/

2. Liu, Chao, Wang, Xiao-Lan, Shen, Er-Chang, Wang, Wen-Jie, Shao, Qiang. . Bioinformatics analysis of prognosis and immune microenvironment of immunological cell death-related gemcitabine-resistance genes in bladder cancer. In Translational andrology and urology, 11, 1715-1728. doi:10.21037/tau-22-736. https://pubmed.ncbi.nlm.nih.gov/36632166/

3. Kalva, Sukesh, Bindusree, Ganigara, Alexander, V, Madasamy, Parani. 2018. Interactome based biomarker discovery for irritable bowel syndrome-A systems biology approach. In Computational biology and chemistry, 76, 218-224. doi:10.1016/j.compbiolchem.2018.07.007. https://pubmed.ncbi.nlm.nih.gov/30071397/

4. Jia, Xiaobin, Liu, Peng, Zhang, Mingxia, Zhao, Huaqian, Jin, Tianbo. 2015. Genetic variants at 6p21, 10q23, 16q21 and 22q12 are associated with esophageal cancer risk in a Chinese Han population. In International journal of clinical and experimental medicine, 8, 19381-7. doi:. https://pubmed.ncbi.nlm.nih.gov/26770579/

5. Graham, Andrew C, Bellou, Eftychia, Harwood, Janet C, Escott-Price, Valentina, Salih, Dervis A. . Human longevity and Alzheimer's disease variants act via microglia and oligodendrocyte gene networks. In Brain : a journal of neurology, 148, 969-984. doi:10.1093/brain/awae339. https://pubmed.ncbi.nlm.nih.gov/39778705/

6. Hu, Nan, Wang, Zhaoming, Song, Xin, Taylor, Philip R, Abnet, Christian C. 2015. Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours. In Gut, 65, 1611-8. doi:10.1136/gutjnl-2015-309340. https://pubmed.ncbi.nlm.nih.gov/26129866/