%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.
%V 588
%A Jaewoong Lee
%A Mark E Robinson
%A Ning Ma
%A Dewan Artadji
%A Mohamed A Ahmed
%A Gang Xiao
%A Teresa Sadras
%A Gauri Deb
%A Janet Winchester
%A Kadriye Nehir Cosgun
%A Huimin Geng
%A Lai N Chan
%A Kohei Kume
%A Teemu P Miettinen
%A Ye Zhang
%A Matthew A Nix
%A Lars Klemm
%A Chun Wei Chen
%A Jianjun Chen
%A Vishal Khairnar
%A Arun P Wiita
%A Andrei Thomas-Tikhonenko
%A Michael Farzan
%A Jae U Jung
%A David M Weinstock
%A Scott R Manalis
%A Michael S Diamond
%A Nagarajan Vaidehi
%A Markus Muschen
%C England
%J Nature
%N 7838
%I NATURE RESEARCH
%L discovery10147988
%D 2020
%P 491-497
%O This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
%T IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells