IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells

Jaewoong Lee, Mark E. Robinson, Ning Ma, Dewan Artadji, Mohamed A. Ahmed, Gang Xiao, Teresa Sadras, Gauri Deb, Janet Winchester, Kadriye Nehir Cosgun, Huimin Geng, Lai N. Chan, Kohei Kume, Teemu P. Miettinen, Ye Zhang, Matthew A. Nix, Lars Klemm, Chun Wei Chen, Jianjun Chen, Vishal Khairnar, Arun P. Wiita, Andrei Thomas-Tikhonenko, Michael Farzan, Jae U. Jung, David M. Weinstock, Scott R. Manalis, Michael S. Diamond, Nagarajan Vaidehi and Markus Müschen ()
Additional contact information
Jaewoong Lee: Yale Cancer Center, Yale School of Medicine
Mark E. Robinson: Yale Cancer Center, Yale School of Medicine
Ning Ma: City of Hope Comprehensive Cancer Center
Dewan Artadji: Yale Cancer Center, Yale School of Medicine
Mohamed A. Ahmed: City of Hope Comprehensive Cancer Center
Gang Xiao: City of Hope Comprehensive Cancer Center
Teresa Sadras: Yale Cancer Center, Yale School of Medicine
Gauri Deb: City of Hope Comprehensive Cancer Center
Janet Winchester: City of Hope Comprehensive Cancer Center
Kadriye Nehir Cosgun: Yale Cancer Center, Yale School of Medicine
Huimin Geng: University of California San Francisco
Lai N. Chan: Yale Cancer Center, Yale School of Medicine
Kohei Kume: Yale Cancer Center, Yale School of Medicine
Teemu P. Miettinen: Massachusetts Institute of Technology
Ye Zhang: Massachusetts Institute of Technology
Matthew A. Nix: University of California San Francisco
Lars Klemm: Yale Cancer Center, Yale School of Medicine
Chun Wei Chen: City of Hope Comprehensive Cancer Center
Jianjun Chen: City of Hope Comprehensive Cancer Center
Vishal Khairnar: City of Hope Comprehensive Cancer Center
Arun P. Wiita: University of California San Francisco
Andrei Thomas-Tikhonenko: University of Pennsylvania
Michael Farzan: The Scripps Research Institute
Jae U. Jung: Lerner Research Institute, Cleveland Clinic
David M. Weinstock: Dana Farber Cancer Institute
Scott R. Manalis: Massachusetts Institute of Technology
Michael S. Diamond: Washington University School of Medicine in St Louis
Nagarajan Vaidehi: City of Hope Comprehensive Cancer Center
Markus Müschen: Yale Cancer Center, Yale School of Medicine

Nature, 2020, vol. 588, issue 7838, 491-497

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2884-6

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