Ncf4, often denoted as p40phox, is a component of the NOX2 complex. It is involved in regulating reactive oxygen species (ROS) production, which is crucial for multiple biological processes, including antigen presentation, inflammasome activation, and immune cell function. Polymorphisms in Ncf4 are associated with various diseases, indicating its importance in disease-related pathways [1-3].

In mice, Ncf4 deficiency leads to severe colorectal cancer. It increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during early colorectal tumorigenesis. Ncf4 also cooperates with Ncf1 and Ncf2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, its phosphorylation and puncta distribution shift from the NADPH complex to the perinuclear region, mediating ASC oligomerization and inflammasome activation [1]. Mice with an Ncf4 amino-acid-replacing mutation (NCF4R58A) have decreased intracellular ROS production, which affects antigen presentation of cysteine peptides, leading to a strong arthritogenic T-cell response, indicating its role in autoimmune arthritis [2]. In another study, Ncf4 mutation in mice enhanced plasma cell formation and autoantibody production, suggesting its role in B-cell terminal differentiation [3].

In conclusion, Ncf4 plays essential roles in regulating immune responses, inflammasome activation, and cell differentiation through ROS-related mechanisms. Mouse models with Ncf4 deficiency or mutation have revealed its significance in diseases such as colorectal cancer, autoimmune arthritis, and potentially others, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Li, Longjun, Mao, Rudi, Yuan, Shenli, Xu, Tao, Qi, Xiaopeng. 2024. NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance. In Nature communications, 15, 5170. doi:10.1038/s41467-024-49549-7. https://pubmed.ncbi.nlm.nih.gov/38886341/

2. Xu, Jing, He, Chang, Cai, Yongsong, Lu, Shemin, Holmdahl, Rikard. 2024. NCF4 regulates antigen presentation of cysteine peptides by intracellular oxidative response and restricts activation of autoreactive and arthritogenic T cells. In Redox biology, 72, 103132. doi:10.1016/j.redox.2024.103132. https://pubmed.ncbi.nlm.nih.gov/38547647/

3. He, Chang, Luo, Huqiao, Coelho, Ana, Yuan, Zuyi, Holmdahl, Rikard. 2022. NCF4 dependent intracellular reactive oxygen species regulate plasma cell formation. In Redox biology, 56, 102422. doi:10.1016/j.redox.2022.102422. https://pubmed.ncbi.nlm.nih.gov/36095971/