%0 Journal Article
%A Lee, Jaewoong
%A Robinson, Mark E
%A Ma, Ning
%A Artadji, Dewan
%A Ahmed, Mohamed A
%A Xiao, Gang
%A Sadras, Teresa
%A Deb, Gauri
%A Winchester, Janet
%A Cosgun, Kadriye Nehir
%A Geng, Huimin
%A Chan, Lai N
%A Kume, Kohei
%A Miettinen, Teemu P
%A Zhang, Ye
%A Nix, Matthew A
%A Klemm, Lars
%A Chen, Chun Wei
%A Chen, Jianjun
%A Khairnar, Vishal
%A Wiita, Arun P
%A Thomas-Tikhonenko, Andrei
%A Farzan, Michael
%A Jung, Jae U
%A Weinstock, David M
%A Manalis, Scott R
%A Diamond, Michael S
%A Vaidehi, Nagarajan
%A Muschen, Markus
%D 2020
%F discovery:10147988
%I NATURE RESEARCH
%J Nature
%N 7838
%P 491-497
%T IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
%U https://discovery.ucl.ac.uk/id/eprint/10147988/
%V 588
%X 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.
%Z This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.