@article{discovery10147988,
         journal = {Nature},
           title = {IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells},
           pages = {491--497},
            note = {This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.},
          volume = {588},
       publisher = {NATURE RESEARCH},
          number = {7838},
            year = {2020},
           month = {December},
        abstract = {Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1,2,3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In B cell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3?/? naive B cells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3?/? B cells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant B cells. Mechanistic experiments revealed that IFITM3 functions as a PIP3 scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3?/? B cells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60 lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after B cells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of B cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.},
          author = {Lee, Jaewoong and Robinson, Mark E and Ma, Ning and Artadji, Dewan and Ahmed, Mohamed A and Xiao, Gang and Sadras, Teresa and Deb, Gauri and Winchester, Janet and Cosgun, Kadriye Nehir and Geng, Huimin and Chan, Lai N and Kume, Kohei and Miettinen, Teemu P and Zhang, Ye and Nix, Matthew A and Klemm, Lars and Chen, Chun Wei and Chen, Jianjun and Khairnar, Vishal and Wiita, Arun P and Thomas-Tikhonenko, Andrei and Farzan, Michael and Jung, Jae U and Weinstock, David M and Manalis, Scott R and Diamond, Michael S and Vaidehi, Nagarajan and Muschen, Markus},
             url = {https://doi.org/10.1038/s41586-020-2884-6}
}