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A proteomic-based approach identifies the NEDD4-adaptor NDFIP2 as an important regulator of IFITM3

ABSTRACT: IFITMs are a family of highly related interferon-induced transmembrane proteins that interfere with the processes of fusion between viral and cellular membranes and are thus endowed with broad antiviral properties. A number of studies have shown how the antiviral potency of IFITMs is highly dependent on their steady-state levels, their intracellular distribution as well as on a complex pattern of post-translational modifications, parameters that are overall tributary of a number of cellular partners. In an effort to identify additional protein partners involved in the biology of IFITMs, we have devised a proteomic-based approach based on the piggyback incorporation of IFITM3 partners into extracellular vesicles. MS analysis of the proteome of vesicles bearing or not IFITM3 identified the NDFIP2 protein adaptor protein as an important regulator of IFITM3 levels. NDFIP2 is a membrane-anchored adaptor protein of E3 ubiquitin ligases of the NEDD4 family that have been already involved in IFITM3 regulation.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yohann Couté

LAB HEAD: Yohann Couté

PROVIDER: PXD043581 | Pride | 2023-10-26

REPOSITORIES: Pride

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Project description:Ifitm3 (interferon-inducible transmembrane protein 3) was previously identified as an endosomal antiviral effector protein that blocks viral infection1-4. In analyses of gene expression data from patients with B-cell leukemia and lymphoma, we identified Ifitm3 as one of the strongest predictors of poor clinical outcome. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, engagement of the B-cell receptor (BCR) and PI3K-activation strongly induced expression of Ifitm3 and phosphorylation of its N-terminus at Y20, resulting in accumulation at the cell surface. In B-cell leukemia, oncogenic kinases induced phosphorylation at Y20, resulting in constitutive plasma membrane localization of Ifitm3. Ifitm3¯ / ¯ naïve B-cells developed at normal numbers, however, B-cell activation upon antigen encounter, germinal center formation and production of antigen-specific antibodies were compromised. Likewise, oncogenes that typically induce development of leukemia and lymphoma failed to transform Ifitm3¯ / ¯ B-cells. Conversely, a phosphomimetic mutation of Y20 induced oncogenic PI3K-signaling and initiated transformation of premalignant B-cells into overt leukemia. Functional experiments revealed a previously unrecognized function of Ifitm3 as PIP3-scaffold and central amplifier of PI3K signaling downstream of the BCR and adhesion receptors. PI3K signal-amplification depends on binding of Ifitm3 to PIP3 via two lysine residues (K83 and K104) in its conserved intracellular loop. In Ifitm3¯ / ¯ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors, which impaired BCR-signaling and cellular adhesion. We conclude that phosphorylation of IFITM3 upon Bcell antigen-encounter induces a dynamic switch from antiviral effector functions in endosomes to a PI3K-amplification loop at the cell surface. IFITM3-dependent amplification of PI3K-signaling downstream of the BCR and adhesion receptors is critical to enable rapid expansion of B-cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3- dependent signaling complexes and amplify PI3K-signaling for malignant transformation.

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A proteomic-based approach identifies the NEDD4-adaptor NDFIP2 as an important regulator of IFITM3

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