Dataset Information

IFITM3-mediated regulation of cell membrane dynamics is essential for malignant B-cell transformation

ABSTRACT: B cell receptor (BCR) signaling and oncogenic tyrosine kinases that mimic BCR-signaling in B-lineage leukemia and lymphoma depend on assembly of membrane proximal signaling complexes. Signalosomes in normal BCR- and oncogene (e.g. BCR-ABL1, RAS-pathway lesions) signal transduction are recruited to phospholipid anchors in lipid rafts. The robustness of these complexes depends on cholesterol accumulation in lipid rafts. Here we identified the interferon-induced transmembrane protein IFITM3 as a central regulator of cholesterol in lipid rafts.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell, Primary Cell, Cell Suspension Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Matthew Nix

LAB HEAD: Arun Wiita

PROVIDER: PXD014691 | Pride | 2020-12-18

REPOSITORIES: Pride

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Publications

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

Lee Jaewoong J Robinson Mark E ME Ma Ning N Artadji Dewan D Ahmed Mohamed A MA Xiao Gang G Sadras Teresa T Deb Gauri G Winchester Janet J Cosgun Kadriye Nehir KN Geng Huimin H Chan Lai N LN Kume Kohei K Miettinen Teemu P TP Zhang Ye Y Nix Matthew A MA Klemm Lars L Chen Chun Wei CW Chen Jianjun J Khairnar Vishal V Wiita Arun P AP Thomas-Tikhonenko Andrei A Farzan Michael M Jung Jae U JU Weinstock David M DM Manalis Scott R SR Diamond Michael S MS Vaidehi Nagarajan N Müschen Markus M

Nature 20201104 7838

Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection<sup>1-3</sup>. 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 prot ...[more]

PMID: 33149299

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Project description:Progression and relapse-free survival of ovarian carcinoma are associated with the abundance of immunosuppressed CD163highCD206high tumor-associated macrophages (TAMs) and high levels of polyunsaturated fatty acids (PUFAs), in particular arachidonic acid (AA), in the tumor microenvironment. In the present study, we have investigated whether both associations are functionally linked. Methods: The effect of PUFAs on cytokine-mediated pro-inflammatory signal transduction was studied in primary monocyte-derived macrophages (MDMs) by transcriptomics, bioinformatics, phosphoprotein analysis of signal transduction proteins and MS-based proteomics of lipid rafts. Results: Pathway analysis of transcriptional profiles revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signal transduction. This is mirrored by an impairment of the transcriptional response to interferon-beta (IFNbeta), IFNgamma and IL-6 in monocyte-derived macrophages (MDMs) by AA. This AA-mediated inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, as indicated by the inhibition by PUFAs of JAK1, JAK2, STAT1 and STAT3 phosphorylation, with the strongest inhibitory effects exerted by AA and its non-metabolizable analog ETYA. AA/ETYA treatment of MDMs results in altered composition of lipid rafts, including reduced amounts of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins. The AA-mediated inhibition of IFN-triggered STAT1 phosphorylation was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by PUFAs. Conclusion: Our data suggest that AA, and to a lesser degree other PUFAs, impair pro-inflammatory signaling in macrophages, at least in part by altering the structure of lipid rafts, and thereby contribute to the reeducation of tumor-associated macrophages. Our findings also suggest that the pharmacologic restoration of lipid raft functions in TAM may be a promising strategy for the development of new therapeutic approaches.

Dataset Information

IFITM3-mediated regulation of cell membrane dynamics is essential for malignant B-cell transformation

Publications

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

Similar Datasets

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