TY  - JOUR
PB  - NATURE RESEARCH
Y1  - 2020/12/17/
VL  - 588
A1  - Lee, Jaewoong
A1  - Robinson, Mark E
A1  - Ma, Ning
A1  - Artadji, Dewan
A1  - Ahmed, Mohamed A
A1  - Xiao, Gang
A1  - Sadras, Teresa
A1  - Deb, Gauri
A1  - Winchester, Janet
A1  - Cosgun, Kadriye Nehir
A1  - Geng, Huimin
A1  - Chan, Lai N
A1  - Kume, Kohei
A1  - Miettinen, Teemu P
A1  - Zhang, Ye
A1  - Nix, Matthew A
A1  - Klemm, Lars
A1  - Chen, Chun Wei
A1  - Chen, Jianjun
A1  - Khairnar, Vishal
A1  - Wiita, Arun P
A1  - Thomas-Tikhonenko, Andrei
A1  - Farzan, Michael
A1  - Jung, Jae U
A1  - Weinstock, David M
A1  - Manalis, Scott R
A1  - Diamond, Michael S
A1  - Vaidehi, Nagarajan
A1  - Muschen, Markus
N2  - 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.
IS  - 7838
JF  - Nature
EP  - 497
AV  - public
ID  - discovery10147988
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
TI  - IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
SP  - 491
UR  - https://doi.org/10.1038/s41586-020-2884-6
ER  -