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IFITM3 amino acid mutants phosphoproteomics

ABSTRACT: To investigate the role of IFITM3 in B-ALL, patient derived xenograft cells PDX2 were transduced with either a the constitutively membrane associated IFITM3-Y20E mutant or EV control. Additional mutation of PIP3 binding sites within the conserved internal loop region - K83/K104 or R85/R87/K88 - were introduced to test the predicted function of these sites.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Mark Robinson

LAB HEAD: Markus Muschen

PROVIDER: PXD020696 | Pride | 2020-12-18

REPOSITORIES: Pride

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			Action	DRS
	200406_30872_AS_L.raw	Raw
	200406_30873_AS_L.raw	Raw
	200406_30874_AS_L.raw	Raw
	200406_30875_AS_L.raw	Raw
	200406_30876_AS_L.raw	Raw

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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

Similar Datasets

Direct analysis of IFITM3 S-fatty-acylation, part 1

Project description:Given our laboratory interest in IFITM3 S-fatty-acylation and antiviral activity, we sought to directly characterize fatty acids that are covalently attached to the Cys residues of IFITM3. IFITM3 comprises two S-fatty-acylation sites (C71 and C72) in proximity of a intramembrane domain, and another site adjacent to a transmembrane domain (C105). We directly identified the S-fatty-acylation sites of IFITM3 and further demonstrated that the highly conserved Cys residues are primarily modified by palmitic acid.

2018-03-28 | PXD008400 | Pride

S6K1 Phosphoproteome in Tsc1-null mouse kidney iMCD3 cells

Project description:Loss of Tsc1 in the kidneys gives rise to rapid polycystogenesis and kidney failure due to the hyperactivation of mTOR complex I (mTORC1). One of the major downstream targets of mTORC1 is S6K1, which is responsible for driving many of the effector functions of mTOR. Strikingly, the loss of S6k1 in the context of hyperactivated mTOR is sufficient to reverse the generation of polycystic kidneys. In an effort to uncover novel direct S6k1 substrates involved in the generation of cystic kidneys, we generated Tsc1-null and Tsc1/S6k1-double null murine inner medullary collecting duct (iMCD3) cell lines using CRISPR/Cas9. Using these two cell lines, we conducted a phosphoproteome screen to search for novel candidates. Using a combination of antibody-motif enrichment and metal affinity enrichment, we provide a comprehensive phosphoproteome profile between these two genotypes.

2020-08-11 | PXD014832 | Pride

Direct analysis of IFITM3 S-fatty-acylation, part 2

Project description:Given our laboratory interest in IFITM3 S-fatty-acylation and antiviral activity, we sought to directly characterize fatty acids that are covalently attached to the Cys residues of IFITM3. IFITM3 comprises two S-fatty-acylation sites (C71 and C72) in proximity of a intramembrane domain, and another site adjacent to a transmembrane domain (C105). We directly identified the S-fatty-acylation sites of IFITM3, and further demonstrated that the highly conserved Cys residues are primarily modified by palmitic acid.

2018-03-28 | PXD008401 | Pride

mTOR orchestrates sequential phases of ependymal cell differentiation by acting on their alternative cell cycle and centrosomal proteins

Project description:Ependymal cells are multiciliated cells lining the brain ventricles, which arise from the differentiation of progenitor cells through the phases of centriole amplification, growth and disengagement phases. Since these commitment phases are accompanied by the sharp up-regulation of mTOR complex 1 activity (mTORC1), a master regulator of macromolecule biosynthesis and cell growth, we address its functional role. We show that mTORC1 inhibition by rapamycin maintains the progenitor pool by reinforcing a quiescent state and blocking the alternative cell cycle progression for centriole amplification. Overexpression of E2F4 and Mcidas bypasses the mTORC1-regulated events and rescues centriole amplification even in the presence of rapamycin, while promoting mTORC1 activity in a positive feed-forward mechanism. Acute rapamycin treatment in multicentriolar cells during the late phases of differentiation causes centriole regrouping, indicating a direct role of mTORC1 on centriole dynamics. By phosphoproteomic and phospho-mutant analysis, we reveal that the mTORC1-mediated phosphorylation of Gas2L1, a centrosomal protein linking actin and microtubule cytoskeletons, participates in the centriole disengagement. This multi-layered and sequential control of ependymal development by mTORC1, from the progenitor pool to the centriolar function, has implications for pathophysiological conditions, such as aging and hydrocephalus-prone genetic diseases.

2025-03-14 | PXD060982 | Pride

PRMT5 methyl proteomics in MiaPaca2 cells

Project description:Goal: To determine total PRMT5 methyl substrates and those that function through the novel substrate adaptor binding site

2022-06-13 | PXD019991 | Pride

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

Project description:Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

2022-07-28 | PXD035254 | Pride

IFITM3 BioID Interactomes in B-ALL and MCL

Project description:To determine the roles of membrane associated IFITM3 in BCR-signalling in B-cell malignancies we expressed N-terminal BirA-IFITM3-Y20E fusion or BirA-EV control in patient derived B-ALL cells (PDX2) and Jeko1 Mantle cell lymphoma (MCL) cells. Additionally to examine the role of PIP3 binding residues in the conserved intracellular loop region a K83A/K104A mutated form of IFITM3-Y20E-BirA fusion and compared with basic patch unmutated.

2020-12-18 | PXD020697 | Pride

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

Project description: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.

2023-10-26 | PXD043581 | Pride

Hat1 WT and Hat1 KO MEFs analyzed to identify sites of acetylation that are dependent on Hat1

Project description:Hat1 WT and Hat1 KO MEFs were grown on both galactose and glucose. Abundance of acetylated peptides was compared between the samples.

2020-02-28 | PXD017362 | Pride

RNA-Seq of influenza A/Puerto Rico/8/1934 (H1N1) virus infected monoclonal cell lines with depressed IFITM3 gene activity

Project description:In this study monoclonal cell lines carrying mutations in IFITM3 gene were obtained based on WI-38 VA13 cells. To research the involvement of the IFITM3 gene in cellular response to Influenza A virus infection, original WI-38 VA13 cells and the clones with depressed IFITM3 gene activity (F3, F5, Е12) were infected with influenza A/Puerto Rico/8/1934 (H1N1) virus. RNA-seq analysis of infected cell lines after 24 h was performed on an Illumina NextSeq 500 platform. The same mock-infected cells were used as controls (0 hpi). PolyA RNA-enriched fraction was used for constructing of cDNA libraries. Differential expressed genes were identified using R package DESeq2.

2023-12-16 | E-MTAB-13582 | biostudies-arrayexpress

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