IFITM3, or interferon-induced transmembrane protein 3, is an endosomal protein. It plays a crucial role in innate immunity, especially in antiviral defense by inhibiting the entry of numerous viruses [1,5]. It is also involved in multiple biological pathways such as those related to inflammation, cancer development, and Alzheimer's disease progression [2,3,4]. Genetic models, like gene knockout (KO) mouse models, have been essential in understanding its functions.

In the context of Alzheimer's disease, the knockout of IFITM3 in a transgenic mouse model (5xFAD) reduced γ-secretase activity and amyloid plaque formation, suggesting it plays a role in promoting amyloid-β production through its interaction with γ-secretase [2]. In B-cell malignancies, Ifitm3-/-naive B-cells in a mouse model showed compromised germinal center formation and antigen-specific antibody production, and oncogenes failed to transform these cells, indicating IFITM3's importance in B-cell transformation and PI3K signaling [8]. In glioblastoma, knockdown of IFITM3 in glioblastoma stem cells could potentially disrupt the JAK/STAT3/bFGF signaling pathway and angiogenesis [6]. In the anti-tumor immunity context, IFITM3-deficient regulatory T cells (Tregs) in a tumor model blunted tumor growth and showed a Th1-like Treg phenotype, highlighting the role of the IFNγ-STAT1-IFITM3 feedback loop in anti-tumor immunity [7].

In conclusion, IFITM3 is a multifunctional protein involved in antiviral defense, inflammation-related tumorigenesis, and Alzheimer's disease. KO mouse models have been instrumental in revealing its role in these disease areas, providing insights into the underlying molecular mechanisms and potential therapeutic targets.

References:

1. Klein, Steffen, Golani, Gonen, Lolicato, Fabio, Schwarz, Ulrich S, Chlanda, Petr. 2023. IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion. In Cell host & microbe, 31, 616-633.e20. doi:10.1016/j.chom.2023.03.005. https://pubmed.ncbi.nlm.nih.gov/37003257/

2. Hur, Ji-Yeun, Frost, Georgia R, Wu, Xianzhong, Goate, Alison, Li, Yue-Ming. 2020. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease. In Nature, 586, 735-740. doi:10.1038/s41586-020-2681-2. https://pubmed.ncbi.nlm.nih.gov/32879487/

3. Lee, Jaewoong. . Does IFITM3 link inflammation to tumorigenesis? In BMB reports, 55, 602-608. doi:. https://pubmed.ncbi.nlm.nih.gov/36404597/

4. Rajapaksa, Ushani S, Jin, Chen, Dong, Tao. 2020. Malignancy and IFITM3: Friend or Foe? In Frontiers in oncology, 10, 593245. doi:10.3389/fonc.2020.593245. https://pubmed.ncbi.nlm.nih.gov/33364194/

5. Jiménez-Munguía, I, Beaven, A H, Blank, P S, Sodt, A J, Zimmerberg, J. 2022. Interferon-induced transmembrane protein 3 (IFITM3) and its antiviral activity. In Current opinion in structural biology, 77, 102467. doi:10.1016/j.sbi.2022.102467. https://pubmed.ncbi.nlm.nih.gov/36306674/

6. Xiong, Zhangsheng, Xu, Xiangdong, Zhang, Yuxuan, Ke, Yiquan, Liu, Yang. 2024. IFITM3 promotes glioblastoma stem cell-mediated angiogenesis via regulating JAK/STAT3/bFGF signaling pathway. In Cell death & disease, 15, 45. doi:10.1038/s41419-023-06416-5. https://pubmed.ncbi.nlm.nih.gov/38218875/

7. Liu, Xinnan, Zhang, Weiqi, Han, Yichao, Li, Hecheng, Li, Bin. 2024. FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity. In Nature communications, 15, 122. doi:10.1038/s41467-023-44391-9. https://pubmed.ncbi.nlm.nih.gov/38167862/

8. Lee, Jaewoong, Robinson, Mark E, Ma, Ning, Vaidehi, Nagarajan, Müschen, Markus. 2020. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. In Nature, 588, 491-497. doi:10.1038/s41586-020-2884-6. https://pubmed.ncbi.nlm.nih.gov/33149299/