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Berlin Brandenburg

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  • 1
    Language: English
    In: Molecular Cell, 11 December 2009, Vol.36(5), pp.831-844
    Description: TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, and is required for efficient TNF-induced activation of NF-κB and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC.
    Keywords: Proteins ; Signaling ; Molimmuno ; Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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  • 2
    In: Nature, 2011, Vol.471(7340), p.591
    Description: Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin^sup cpdm/cpdm^) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling. [PUBLICATION ]
    Keywords: Animals–Metabolism ; Cd40 Ligand–Chemistry ; Carrier Proteins–Metabolism ; Carrier Proteins–Metabolism ; Cell Line–Immunology ; Humans–Metabolism ; I-Kappa B Kinase–Pathology ; Immunity–Prevention & Control ; Inflammation–Metabolism ; Inflammation–Chemistry ; Inflammation–Metabolism ; Interleukin-1beta–Metabolism ; Mice–Chemistry ; Multiprotein Complexes–Genetics ; Multiprotein Complexes–Metabolism ; Nf-Kappa B–Metabolism ; Nerve Tissue Proteins–Deficiency ; Nerve Tissue Proteins–Genetics ; Nerve Tissue Proteins–Metabolism ; Phenotype–Cytology ; Receptor-Interacting Protein Serine-Threonine Kinases–Immunology ; Receptors, Tumor Necrosis Factor–Metabolism ; Receptors, Tumor Necrosis Factor–Pathology ; Receptors, Tumor Necrosis Factor–Deficiency ; Signal Transduction–Genetics ; Skin–Chemistry ; Skin–Metabolism ; Skin–Chemistry ; Skin–Metabolism ; Tumor Necrosis Factor-Alpha–Chemistry ; Tumor Necrosis Factor-Alpha–Metabolism ; Ubiquitin–Metabolism ; Ubiquitin–Metabolism ; Ubiquitin-Protein Ligase Complexes–Metabolism ; Ubiquitin-Protein Ligase Complexes–Metabolism ; Ubiquitin-Protein Ligases–Metabolism ; Ubiquitin-Protein Ligases–Metabolism ; Ubiquitination–Metabolism ; Mutation ; Apoptosis ; Proteins ; Recruitment ; Disease ; Carrier Proteins ; Ikbkg Protein, Human ; Interleukin-1beta ; Multiprotein Complexes ; Nf-Kappa B ; Nerve Tissue Proteins ; Rnf31 Protein, Human ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-Alpha ; Ubiquitin ; Sharpin ; Cd40 Ligand ; Ripk1 Protein, Human ; Receptor-Interacting Protein Serine-Threonine Kinases ; I-Kappa B Kinase ; Hoil-1 Protein, Human ; Ubiquitin-Protein Ligase Complexes ; Ubiquitin-Protein Ligases;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    Language: English
    In: Molecular & cellular proteomics : MCP, May 2018, Vol.17(5), pp.993-1009
    Description: Coimmunoprecipitation (co-IP) is one of the most frequently used techniques to study protein-protein (PPIs) or protein-nucleic acid interactions (PNIs). However, the presence of coprecipitated contaminants is a well-recognized issue associated with single-step co-IPs. To overcome this limitation, we developed the two-step co-IP (TIP) strategy that enables sequential coimmunoprecipitations of endogenous protein complexes. TIP can be performed with a broad range of mono- and polyclonal antibodies targeting a single protein or different components of a given complex. TIP results in a highly selective enrichment of protein complexes and thus outperforms single-step co-IPs for downstream applications such as mass spectrometry for the identification of PPIs and quantitative PCR for the analysis of PNIs. We benchmarked TIP for the identification of CD95/FAS-interacting proteins in primary human CD4 T cells, which recapitulated all major known interactors, but also enabled the proteomics discovery of PPM1G and IPO7 as new interaction partners. For its feasibility and high performance, we propose TIP as an advanced tool for the isolation of highly purified protein-protein and protein-nucleic acid complexes under native expression conditions.
    Keywords: Biology ; Anatomy & Physiology;
    ISSN: 15359476
    E-ISSN: 1535-9484
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  • 4
    Language: English
    In: Cell Stem Cell, 06 July 2017, Vol.21(1), pp.35-50.e9
    Description: Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target. Haas et al. identify integrin α7 as a functional marker of glioblastoma stem cells by screening a monoclonal antibody library generated against primary glioblastoma (GBM) cells. Functional experiments in culture and in vivo show that the targeting of integrin α7 has potential as a therapeutic avenue for treating this aggressive disease.
    Keywords: High Throughput Screening ; Monoclonal Antibody ; Mab ; Cancer Stem Cell Marker ; Glioblastoma Cell Invasion ; Biomarker ; Biology
    ISSN: 1934-5909
    E-ISSN: 1875-9777
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