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

Autor: Lee J; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Robinson ME; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Ma N; Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Artadji D; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Ahmed MA; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Xiao G; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Sadras T; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Deb G; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Winchester J; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Cosgun KN; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Geng H; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Chan LN; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Kume K; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Miettinen TP; 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., Zhang Y; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Nix MA; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Klemm L; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Chen CW; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Chen J; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Khairnar V; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Wiita AP; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Thomas-Tikhonenko A; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Farzan M; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA., Jung JU; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Weinstock DM; Dana Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Manalis SR; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Diamond MS; 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., Vaidehi N; Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Müschen M; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. markus.muschen@yale.edu.; Department of Immunobiology, Yale University, New Haven, CT, USA. markus.muschen@yale.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Dec; Vol. 588 (7838), pp. 491-497. Date of Electronic Publication: 2020 Nov 04.
DOI: 10.1038/s41586-020-2884-6
Abstrakt: Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection 1-3 . 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.
Databáze: MEDLINE
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