CYB5R4, also known as cytochrome b5 reductase 4, is an orphan reductase that acts as an evolutionarily conserved activator of PP4 and PP6, crucial for the regulation of intracellular signaling. It is involved in processes such as energy-balance regulation, and its function requires heme binding to reduce metal ions in the active site of PP4 and PP6 [5].

In podocytes, siRNA silencing of CYB5R4 led to a significant down-regulation of CD2AP and synaptopodin, indicating its importance in maintaining podocyte cytoskeleton structure and function [1]. In infertile men, CYB5R4 was among the genes that were remarkably under-expressed, suggesting its potential role in gametogenesis, fertilization, and embryo development [2]. In Jiaxian Red cattle and Bohai Black cattle, CYB5R4 was associated with meat quality traits, such as those related to fat deposition [3,4]. In Japanese Black cattle, polymorphisms in CYB5R4 were significantly associated with the oleic acid percentage [6]. In chickens, CYB5R4 was among the genes associated with fatty acid composition in breast meat [7].

In conclusion, CYB5R4 plays essential roles in multiple biological processes, including cell-specific cytoskeleton maintenance, reproductive processes in humans, and meat-related traits in livestock. Its study through functional assays like siRNA silencing in cells and analysis of gene expression and polymorphisms in different species has provided insights into its significance in these biological functions and disease-related conditions.

References:

1. Lu, Yuqiu, Ye, Yuting, Bao, Wenduona, Liu, Zhihong, Shi, Shaolin. 2017. Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing. In Kidney international, 92, 1119-1129. doi:10.1016/j.kint.2017.04.022. https://pubmed.ncbi.nlm.nih.gov/28709640/

2. Cheung, Stephanie, Parrella, Alessandra, Rosenwaks, Zev, Palermo, Gianpiero D. 2019. Genetic and epigenetic profiling of the infertile male. In PloS one, 14, e0214275. doi:10.1371/journal.pone.0214275. https://pubmed.ncbi.nlm.nih.gov/30897172/

3. Xia, Xiaoting, Zhang, Shunjin, Zhang, Huaju, Chen, Hong, Huang, Yongzhen. 2021. Assessing genomic diversity and signatures of selection in Jiaxian Red cattle using whole-genome sequencing data. In BMC genomics, 22, 43. doi:10.1186/s12864-020-07340-0. https://pubmed.ncbi.nlm.nih.gov/33421990/

4. Ma, Xiaohui, Cheng, Haijian, Liu, Yangkai, Song, Enliang, Lei, Chuzhao. 2022. Assessing Genomic Diversity and Selective Pressures in Bohai Black Cattle Using Whole-Genome Sequencing Data. In Animals : an open access journal from MDPI, 12, . doi:10.3390/ani12050665. https://pubmed.ncbi.nlm.nih.gov/35268233/

5. Meeusen, Bob, Ambjørn, Sara M, Veis, Jiri, Ogris, Egon, Nilsson, Jakob. 2025. A functional map of phosphoprotein phosphatase regulation identifies an evolutionary conserved reductase for the catalytic metal ions. In bioRxiv : the preprint server for biology, , . doi:10.1101/2025.02.12.637884. https://pubmed.ncbi.nlm.nih.gov/39990307/

6. Kawaguchi, Fuki, Kigoshi, Hiroto, Fukushima, Moriyuki, Mannen, Hideyuki, Sasazaki, Shinji. 2019. Whole-genome resequencing to identify candidate genes for the QTL for oleic acid percentage in Japanese Black cattle. In Animal science journal = Nihon chikusan Gakkaiho, 90, 467-472. doi:10.1111/asj.13179. https://pubmed.ncbi.nlm.nih.gov/30780197/

7. Cho, Eunjin, Kim, Minjun, Cho, Sunghyun, Jin, Daehyeok, Lee, Jun Heon. 2023. A genome-wide association study for the fatty acid composition of breast meat in an F2 crossbred chicken population. In Journal of animal science and technology, 65, 735-747. doi:10.5187/jast.2023.e1. https://pubmed.ncbi.nlm.nih.gov/37970507/