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Berlin Brandenburg

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  • 1
    Language: English
    In: Nature, May 2018, Vol.557(7703), pp.112-117
    Description: The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1 (also known as Rbck1) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3Casp8Hoil-1 embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.
    Keywords: Cell Death ; Embryonic Development ; Hematopoiesis ; Carrier Proteins -- Metabolism ; Ubiquitin -- Metabolism ; Ubiquitin-Protein Ligases -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 2
    Language: English
    In: Trends in biochemical sciences, 2013, Vol.38(2), pp.94-102
    Description: Ubiquitination is a post-translational modification that creates versatility in cell signalling, in part because eight biochemically different inter-ubiquitin linkages can be formed through the seven internal lysine residues of ubiquitin or its amino-terminal methionine. The latter, referred to as linear or M1 linkage, is created by the linear ubiquitin chain assembly complex (LUBAC). Previously, K63 linkages were thought to be exclusively responsible for ubiquitin-mediated nondegradative functions. It now emerges, however, that M1 ubiquitination is crucial in various pathways, and that generation of a physiological signalling output requires cooperation between different ubiquitin linkage types. Here, we review the currently known functions of LUBAC and M1 ubiquitination, discuss promising future research directions into their functions, and how this may reveal novel therapeutic opportunities for diseases with perturbed linear ubiquitination. ; p. 94-102.
    Keywords: Ubiquitination ; Methionine ; Lysine ; Cell Communication ; Ubiquitin
    ISSN: 0968-0004
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  • 3
    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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  • 4
    Language: English
    In: Trends in Biochemical Sciences, February 2013, Vol.38(2), pp.94-102
    Description: Ubiquitination is a post-translational modification that creates versatility in cell signalling, in part because eight biochemically different inter-ubiquitin linkages can be formed through the seven internal lysine residues of ubiquitin or its amino-terminal methionine. The latter, referred to as linear or M1 linkage, is created by the linear ubiquitin chain assembly complex (LUBAC). Previously, K63 linkages were thought to be exclusively responsible for ubiquitin-mediated nondegradative functions. It now emerges, however, that M1 ubiquitination is crucial in various pathways, and that generation of a physiological signalling output requires cooperation between different ubiquitin linkage types. Here, we review the currently known functions of LUBAC and M1 ubiquitination, discuss promising future research directions into their functions, and how this may reveal novel therapeutic opportunities for diseases with perturbed linear ubiquitination.
    Keywords: Linear Ubiquitination ; Lubac ; Sharpin ; Hoil-1 ; Hoip ; Rbr E3 Ligases ; Tnfsignalling ; Biology
    ISSN: 0968-0004
    E-ISSN: 1362-4326
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  • 5
    Language: English
    In: Nature cell biology, December 2018, Vol.20(12), pp.1389-1399
    Description: The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain...
    Keywords: I-Kappa B Kinase -- Metabolism ; Protein-Serine-Threonine Kinases -- Metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases -- Metabolism ; Tumor Necrosis Factor-Alpha -- Pharmacology
    ISSN: 14657392
    E-ISSN: 1476-4679
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  • 6
    Dissertation
    Dissertation
    Imperial College London
    Description: Members of the tumour necrosis factor receptor (TNFR) superfamily, the interleukin-1 Receptor (IL-1R), the Toll-like Receptor (TLR) and the NOD-like receptor (NLRs) families play crucial roles in the initiation of innate immune responses. Even though the stimulation of these different receptors is triggered by upstream signalling components which are largely receptor-specific, their signalling cascades generally converge in the activation of both mitogen-activated protein kinases (MAPKs) and the inhibitor of nuclear factor– B (I B) kinases (IKKs). The activation of MAPKs and IKKs are crucial events in the signalling cascades of TNFR-, IL-1R-, TLR- and NLR family members and result in the activation of distinct transcription factors such as AP-1 and NF- B, respectively. In order to gain a more comprehensive picture of the signalling components associated with TNFR1 our group developed a modified tandem affinity purification (moTAP) strategy. This led to the identification of three novel components of the native TNFR1 signalling complex (TNFRSC): HOIL-1, HOIP and SHARPIN. Together, they form the “linear ubiquitin chain assembly complex” (LUBAC), a tripartite E3 ligase complex which generates linear ubiquitin chains. LUBAC activity is required for efficient TNF-mediated activation of NF- B and JNK by linearly ubiquitinating NEMO and RIP1 in the TNF-RSC. Mutation of the SHARPIN-encoding gene in mice results in chronic proliferative dermatitis (cpdm). The cpdm phenotype is characterised by inflammatory skin lesions and defective lymphoid organogenesis. In this thesis it is shown that mouse embryonic fibroblasts (MEFs) and primary keratinocytes generated from cpdm mice showed impaired activation of the MAPK- and NF- B signalling pathways following stimulation by various TNF and IL-1 family members as well as by different TLR ligands. These alterations were also apparent in bone marrow-derived macrophages isolated from cpdm mice. Thereby, lack of SHARPIN exerted an inhibitory effect on gene-activatory signal transduction by these immune stimuli. Similar defects in NF- B and MAPK signalling were also observed with a ligand for the NLR family member NOD2. Cells generated from mice conditionally deficient for the other LUBAC components exhibited similar alterations in diverse innate immune signalling pathways. These results imply that SHARPIN and HOIL-1 cannot substitute each other but instead cooperate with HOIP to generate linear ubiquitin chains in the signalling pathways that are activated by diverse immune receptors. In summary, the results of this thesis identify LUBAC and the linear ubiquitin chains it generates as previously unrecognised components of various signalling pathways which are central to the induction of immunity and regulation of inflammation.
    Keywords: 610
    Source: Networked Digital Library of Theses and Dissertations
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  • 7
    Dissertation
    Dissertation
    Imperial College London
    Language: English
    Description: Members of the tumour necrosis factor receptor (TNFR) superfamily, the interleukin-1 Receptor (IL-1R), the Toll-like Receptor (TLR) and the NOD-like receptor (NLRs) families play crucial roles in the initiation of innate immune responses. Even though the stimulation of these different receptors is triggered by upstream signalling components which are largely receptor-specific, their signalling cascades generally converge in the activation of both mitogen-activated protein kinases (MAPKs) and the inhibitor of nuclear factor– B (I B) kinases (IKKs). The activation of MAPKs and IKKs are crucial events in the signalling cascades of TNFR-, IL-1R-, TLR- and NLR family members and result in the activation of distinct transcription factors such as AP-1 and NF- B, respectively. In order to gain a more comprehensive picture of the signalling components associated with TNFR1 our group developed a modified tandem affinity purification (moTAP) strategy. This led to the identification of three novel components of the native TNFR1 signalling complex (TNFRSC): HOIL-1, HOIP and SHARPIN. Together, they form the “linear ubiquitin chain assembly complex” (LUBAC), a tripartite E3 ligase complex which generates linear ubiquitin chains. LUBAC activity is required for efficient TNF-mediated activation of NF- B and JNK by linearly ubiquitinating NEMO and RIP1 in the TNF-RSC. Mutation of the SHARPIN-encoding gene in mice results in chronic proliferative dermatitis (cpdm). The cpdm phenotype is characterised by inflammatory skin lesions and defective lymphoid organogenesis. In this thesis it is shown that mouse embryonic fibroblasts (MEFs) and primary keratinocytes generated from cpdm mice showed impaired activation of the MAPK- and NF- B signalling pathways following stimulation by various TNF and IL-1 family members as well as by different TLR ligands. These alterations were also apparent in bone marrow-derived macrophages isolated from cpdm mice. Thereby, lack of SHARPIN exerted an inhibitory effect on gene-activatory signal transduction by these immune stimuli. Similar defects in NF- B and MAPK signalling were also observed with a ligand for the NLR family member NOD2. Cells generated from mice conditionally deficient for the other LUBAC components exhibited similar alterations in diverse innate immune signalling pathways. These results imply that SHARPIN and HOIL-1 cannot substitute each other but instead cooperate with HOIP to generate linear ubiquitin chains in the signalling pathways that are activated by diverse immune receptors. In summary, the results of this thesis identify LUBAC and the linear ubiquitin chains it generates as previously unrecognised components of various signalling pathways which are central to the induction of immunity and regulation of inflammation.
    Keywords: 610
    Source: The British Library
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  • 8
    Language: English
    In: Advances in experimental medicine and biology, 2011, Vol.691, pp.115-26
    Keywords: Signal Transduction ; Transcriptional Activation ; Apoptosis -- Genetics ; Multiprotein Complexes -- Metabolism ; Receptors, Tumor Necrosis Factor, Type I -- Metabolism ; Tumor Necrosis Factor-Alpha -- Metabolism ; Ubiquitin -- Metabolism
    ISBN: 9781441966117
    ISSN: 0065-2598
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 9
    In: EMBO Journal, 02 September 2002, Vol.21(17), pp.4520-4530
    Description: The involvement of the death adaptor protein FADD and the apoptosis‐initiating caspase‐8 in CD95 and TRAIL death signalling has recently been demonstrated by the analysis of the native death‐inducing signalling complex (DISC) that forms upon ligand‐induced receptor cross‐linking. However, the role of caspase‐10, the other death‐effector‐domain‐containing caspase besides caspase‐8, in death receptor signalling has been controversial. Here we show that caspase‐10 is recruited not only to the native TRAIL DISC but also to the native CD95 DISC, and that FADD is necessary for its recruitment to and activation at these two protein complexes. With respect to the function of caspase‐10, we show that it is not required for apoptosis induction. In addition, caspase‐10 can not substitute for caspase‐8, as the defect in apoptosis induction observed in caspase‐8‐deficient cells could not be rescued by overexpression of caspase‐10. Finally, we demonstrate that caspase‐10 is cleaved during CD95‐induced apoptosis of activated T cells. These results show that caspase‐10 activation occurs in primary cells, but that its function differs from that of caspase‐8.
    Keywords: Caspase ; Cd95 Apo‐1/Fas ; Death‐Inducing Signalling Complex ; Death Receptor ; Trail
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 10
    Language: English
    In: The Journal of experimental medicine, 14 November 2016, Vol.213(12), pp.2671-2689
    Description: The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1-interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.
    Keywords: Signal Transduction ; Immunologic Deficiency Syndromes -- Metabolism ; Inflammation -- Pathology ; Nerve Tissue Proteins -- Metabolism ; Toll-Like Receptor 3 -- Metabolism ; Transcription Factors -- Metabolism ; Ubiquitin-Protein Ligases -- Metabolism
    E-ISSN: 1540-9538
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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