IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
Authors: Ye Zhang
David M Weinstock
Kohei Kume
Matthew A Nix
Andrei Thomas-Tikhonenko
Jianjun Chen
Chun Wei Chen
Jae U Jung
Kadriye Nehir Cosgun
Jaewoong Lee
Michael S Diamond
Gang Xiao
Scott R Manalis
Michael Farzan
Mohamed A Ahmed
Nagarajan Vaidehi
Lars Klemm
Ning Ma
Dewan Artadji
Markus Müschen
Lai N Chan
Arun P Wiita
Huimin Geng
Teemu P Miettinen
Mark E Robinson
Janet Winchester
Teresa Sadras
Vishal Khairnar
Gauri Deb
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: IFITM3; B cell leukaemia; lymphoma; B cell receptor; phosphorylation
Affiliations: Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, UK., Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Dana Farber Cancer Institute, Boston, MA, USA., Harvard Medical School, Boston, MA, USA., Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Department of Medicine, Washington University School of Medicine in St Louis, St Louis, MO, USA., Department of Molecular Microbiology, Washington University School of Medicine in St Louis, St Louis, MO, USA., Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, MO, USA., Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. ., Department of Immunobiology, Yale University, New Haven, CT, USA. .

Abstract:  Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1-3. 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. 

Retracted: No

PubPeer comments:
 ![file] Could authors explain the similarity in Extended Fig. 7Auff1fAlso, I noticd different magnification shared same scale bar (red box). , 
 Published online 04 November 2020 In this Article, the y-axis labels (0 and 14) for chromatin immunoprecipitation with sequencing (ChIPu2013seq) enrichment shifted during resizing of Extended Data Fig. 1m. Figure 1 of this Amendment shows the original and corrected lower panel. For the experiments shown in Extended Data Fig. 7a, images were taken at 4u00d7 (500 u03bcm scale bar) and 10u00d7 (200 u03bcm scale bar) magnification. The scale bars for the 4u00d7 magnification images shown in Extended Data Fig. 7a were incorrectly labelled u2018200 u03bcmu2019. In addition, the original photomicrograph in Extended Data Fig. 7a labelled with the condition u2018+Ifitm3Y20E-HA; anti-CD19u2019 was taken at 10u00d7 magnification while the 4u00d7 magnification image of the same condition was inadvertently shown as the u2018+Ifitm3Y20E-HA; anti-HAu2019 condition. Figure 2 of this Amendment shows the original and corrected Extended Data Fig. 7a. Extended Data Figs. 1 and 7 of the original Article have been corrected online. ,