CYBB, also known as NOX2 or gp91phox, encodes a component of the Phagocytic Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This enzyme is crucial for generating superoxide, which serves as a precursor for hydrogen peroxide and other reactive oxygen species (ROS) in neutrophils [3,5]. The ROS production is essential for killing bacteria and other microorganisms, and also plays a role in regulating the inflammatory response [3]. Mutations in CYBB can lead to X-linked chronic Granulomatous Disease (CGD), highlighting its importance in the immune system [5]. Genetic models, such as CYBB knockout models, can be useful for studying its function [6].

In sepsis, machine learning analysis identified CYBB as an independent predictor of poor survival in patients, suggesting it could be a biomarker and potential treatment target. Sulforaphane treatment in mice alleviated lung NETs expression and injury, accompanied by a change in whole blood CYBB mRNA level [1]. In Mycobacterium leprae-infected macrophages, CYBB-mediated ferroptosis was associated with M2 polarization, facilitating the immune escape and growth of the bacteria [2]. In mesenchymal glioblastoma, CYBB conferred chemotherapy and ferroptosis resistance via modulating the Nrf2/SOD2 axis [4]. Mutations in CYBB cause X-linked CGD in Pakistani patients, with specific mutations identified in different exons of the gene [5]. A CRISPR-gene-engineered CYBB knockout PLB-985 cell model was used to study the functional impact of X-linked CGD mutations [6].

In conclusion, CYBB is essential for the function of the NADPH oxidase complex, playing a key role in immune-related processes like pathogen killing, inflammation regulation, and macrophage polarization. Its dysregulation is associated with diseases such as sepsis, leprosy, glioblastoma, and X-linked CGD. The use of knockout models, both in cells and potentially in mice, has been valuable in understanding how CYBB contributes to these disease conditions, providing insights into potential therapeutic strategies.

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. Winterbourn, Christine C, Kettle, Anthony J, Hampton, Mark B. 2016. Reactive Oxygen Species and Neutrophil Function. In Annual review of biochemistry, 85, 765-92. doi:10.1146/annurev-biochem-060815-014442. https://pubmed.ncbi.nlm.nih.gov/27050287/

4. 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/

5. 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/

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/