CYBB, also known as NOX2 or gp91phox, encodes a component of the phagocytic Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This enzyme is responsible for transferring electrons from intracellular NADPH to extracellular oxygen, generating superoxide anions crucial for killing pathogens. The activation of phagocyte NADPH oxidase requires the membrane translocation and binding of several cytosolic factors [5].

In sepsis, CYBB, along with FCAR, was identified as an independent predictor of poor survival in patients. Sulforaphane (SFN) significantly alleviated murine lung neutrophil extracellular trap (NETs) expression and injury, accompanied by a decrease in whole blood CYBB mRNA level, suggesting CYBB could be a potential target for sepsis treatment [1]. In Mycobacterium leprae-infected monocyte-derived macrophages, CYBB-mediated ferroptosis was found to be associated with immunosuppression, promoting M2 polarization of macrophages and facilitating the immune escape and growth of the pathogen [2]. In mesenchymal glioblastoma, the CYBB subunit of NADPH oxidase confers chemotherapy and ferroptosis resistance via modulation of the Nrf2/SOD2 axis [3]. Mutations in CYBB cause X-linked chronic granulomatous disease (CGD), leading to susceptibility to recurrent fungal and bacterial infections [4].

In conclusion, CYBB plays essential roles in immune-related functions, such as pathogen killing and macrophage polarization. Its involvement in various disease conditions like sepsis, leprosy, glioblastoma, and CGD has been revealed through multiple studies. The use of models like gene-engineered CYBB knockout PLB-985 cells has contributed to understanding the functional impact of CYBB mutations in CGD diagnosis [6]. Overall, CYBB is a crucial gene in understanding immune-related disease mechanisms.

References:

1. You, GuoHua, Zhao, XueGang, Liu, JianRong, Sui, Xin, Yi, HuiMin. 2023. Machine learning-based identification of CYBB and FCAR as potential neutrophil extracellular trap-related treatment targets in sepsis. In Frontiers in immunology, 14, 1253833. doi:10.3389/fimmu.2023.1253833. https://pubmed.ncbi.nlm.nih.gov/37901228/

2. Wang, Zhe, Liu, Tingting, Wang, Zhenzhen, Liu, Hong, Zhang, Furen. 2023. CYBB-Mediated Ferroptosis Associated with Immunosuppression in Mycobacterium leprae-Infected Monocyte-Derived Macrophages. In The Journal of investigative dermatology, 144, 874-887.e2. doi:10.1016/j.jid.2023.10.012. https://pubmed.ncbi.nlm.nih.gov/37925067/

3. Su, I-Chang, Su, Yu-Kai, Setiawan, Syahru Agung, Lin, Chien-Min, Liu, Heng-Wei. 2023. NADPH Oxidase Subunit CYBB Confers Chemotherapy and Ferroptosis Resistance in Mesenchymal Glioblastoma via Nrf2/SOD2 Modulation. In International journal of molecular sciences, 24, . doi:10.3390/ijms24097706. https://pubmed.ncbi.nlm.nih.gov/37175412/

4. Gul, Irum, Khan, Taj Ali, Akbar, Noor Ul, Ali, Rehman, Khan, Shahid Niaz. 2023. Novel mutations in CYBB Gene Cause X-linked chronic Granulomatous Disease in Pakistani patients. In Italian journal of pediatrics, 49, 95. doi:10.1186/s13052-023-01496-7. https://pubmed.ncbi.nlm.nih.gov/37533075/

5. Liu, Xiaoyu, Shi, Yiting, Liu, Rui, Song, Kangcheng, Chen, Lei. 2024. Structure of human phagocyte NADPH oxidase in the activated state. In Nature, 627, 189-195. doi:10.1038/s41586-024-07056-1. https://pubmed.ncbi.nlm.nih.gov/38355798/

6. Beaumel, Sylvain, Verbrugge, Lucile, Fieschi, Franck, Stasia, Marie José. . CRISPR-gene-engineered CYBB knock-out PLB-985 cells, a useful model to study functional impact of X-linked chronic granulomatous disease mutations: application to the G412E X91+-CGD mutation. In Clinical and experimental immunology, 212, 156-165. doi:10.1093/cei/uxad028. https://pubmed.ncbi.nlm.nih.gov/36827093/