Transcriptional profiling of post-positive selection thymocytes from HOIL- and SHARPIN-deficient mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE74552 | GEO | 2016/10/30
SECONDARY ACCESSION(S): PRJNA300687
REPOSITORIES: GEO
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Project description:One of the ubiquitin ligases, LUBAC, is a trimetric complex composed of SHARPIN, HOIL-1, and HOIP. LUBAC works at the proximal TCR signaling pathway allowing normal Treg development. We used microarrays to detail the global programme of gene expression underlying LUBAC-mediated signaling pathway in Treg cells.
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Project description:The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss of Sharpin leads to severe dermatitis due to excessive cell death in keratinocytes. Here we report two patients with SHARPIN deficiency manifesting autoinflammatory symptoms but unexpectedly, no dermatologic manifestations. Patient fibroblasts and B cells showed attenuated canonical NF-κB response and propensity to cell death mediated by TNF superfamily members. Both SHARPIN- and HOIP-deficient patients showed substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
2024-03-07 | GSE261031 | GEO
Project description:Sharpin, a multifunctional adaptor protein with oncogenic properties, regulates several signalling pathways. For example, Sharpin enhances signal-induced NF-κB signalling as part of the linear ubiquitin assembly complex (LUBAC) and inhibits integrins, the T cell receptor, caspase1 and PTEN. However, despite recent insights into Sharpin and LUBAC function, a systematic approach to identify signalling pathways regulated by Sharpin has not been reported. Here, we present the first ‘Sharpin interactome’, which identifies a large amount of novel potential Sharpin interactors. These data suggest that Sharpin and LUBAC might regulate a larger number of biological processes than previously identified, such as endosomal trafficking, RNA processing, metabolism and cytoskeleton regulation. Importantly, using the Sharpin interactome we have identified a novel role for Sharpin in lamellipodium formation. We demonstrate that Sharpin interacts with the Arp2/3 complex, a protein complex that catalyses actin filament branching, and that Sharpin and Arp2/3 colocalize in lamellipodia. We identified the Arp2/3-binding site in Sharpin and demonstrate using a specific Arp2/3-binding deficient mutant that the Sharpin-Arp2/3 interaction promotes lamellipodia formation in a LUBAC-independent fashion.
2017-08-11 | PXD004734 | Pride
Project description:Identification of LUBAC interactors. Analysis of HOIL-1, HOIP and Sharpin N and C terminal interactors
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Project description:We aim to investigate the role of SHARPIN in breast cancer progression. MCF-7 cells were used as the model and SHARPIN was silenced by siRNA.SHARPIN (SHANK-Associated RH Domain Interactor) is also named as SIPL1 and HSIPL1. The gene is located in Chr 8. SHARPIN protein is shown to regulate cell adhesion and migration. Besides, SHARPIN is proved to the component of the LUBAC complex and is necessary for NKFB function, while SHARPIN KO mice will lead to chronic dermatitis and immune deficiency in B cells.
2017-01-01 | GSE77261 | GEO
Project description:To investigate the role of LUBAC in the development and maintenance of the thymic epithelail cells, we analysed the transcriptional changes that result from loss of HOIL - a critical component of the LUBAC protein complex rnecessary for complex assembly, stability and therefore function - in purified mouse thymic epithelial cell populations.
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Project description:HOIL-1L is an essential member of the linear ubiquitin assembly complex (LUBAC), which targets Nemo for linear ubiquitination during NF-kB activation in response to a variety of simuli, including LPS and TNFa treatment. HOIL-1L has also been suggested to function as a transcription factor. Here we analyzed changes in the global transcriptional profiles of primary bone marrow derived macrophage (BMDMs) from WT and HOIL-1L-/- mice upon treatment with NF-kB activating simuli.
2014-05-15 | GSE57180 | GEO
Project description:HOIL-1L is an essential member of the linear ubiquitin assembly complex (LUBAC), which targets Nemo for linear ubiquitination during NF-kB activation in response to a variety of simuli, including LPS and TNFa treatment. HOIL-1L has also been suggested to function as a transcription factor. Here we analyzed changes in the global transcriptional profiles of primary bone marrow derived macrophage (BMDMs) from WT and HOIL-1L-/- mice upon treatment with NF-kB activating simuli. BMDMs were differentiated for 1 week and then treated with mock (untreated), 10ng/ml LPS, or 1ng/ml TNFa for 4 hours. RNA was immediately collected and analyzed in biological duplicates by the Agilent 8x60 mouse array.
2014-05-15 | E-GEOD-57180 | biostudies-arrayexpress
Project description:The linear ubiquitin chain assembly complex (LUBAC) is the only known ubiquitin ligase that generates linear/Met1-linked ubiquitin chains. One of the LUBAC components, HOIL-1L, was recently shown to catalyse oxyester bond formation between the C-terminus of ubiquitin and some substrates. However, oxyester bond formation in the context of LUBAC has not been directly observed. We present the first 3D reconstruction of LUBAC obtained by electron microscopy and report its generation of heterotypic ubiquitin chains containing linear linkages with oxyester-linked branches. We found that addition of the oxyester-bound branches depends on HOIL-1L catalytic activity. We suggest a coordinated ubiquitin relay mechanism between the HOIP and HOIL-1L ligases supported by cross-linking mass spectrometry data, which show proximity between the catalytic RBR domains. Mutations in the linear ubiquitin chain-binding NZF domain of HOIL-1L reduces chain branching confirming its role in the process. In cells, these heterotypic chains were induced by TNF. In conclusion, we demonstrate that LUBAC assembles heterotypic ubiquitin chains with linear and oxyester-linked branches by the concerted action of HOIP and HOIL-1L.
2021-06-28 | PXD019771 | Pride
Project description:The cytosolic protein Sharpin is as a component of the linear ubiquitin chain assembly complex (LUBAC), which regulates NF-κB signaling in response to specific ligands. Its inactivating mutation in Cpdm (chronic proliferative dermatitis mutation) mice causes multi-organ inflammation, yet this phenotype is not transferable into wildtype mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, but the cellular and molecular causes of this phenotype remained to be established. Here we have applied non-decalcified histology together with cellular and dynamic histomorphometry to perform a thorough skeletal phenotyping of Cpdm mice. We show that Cpdm mice display trabecular and cortical osteopenia, solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. We additionally found that Cpdm mice display a severe disturbance of articular cartilage integrity in the absence of joint inflammation, supporting the concept that Sharpin-deficiency affects mesenchymal cell differentiation. Consistently, Cpdm mesenchymal cells displayed reduced osteogenic capacitiy ex vivo, yet this defect was not associated with impaired NF-κB signaling. A molecular comparison of wildtype and Cpdm bone marrow cell populations further revealed that Cpdm mesenchymal cells produce higher levels of Cxcl5 and lower levels of IL1ra. Collectively, our data demonstrate that skeletal defects of Cpdm mice are not caused by chronic inflammation, but that Sharpin is as a critical regulator of mesenchymal cell differentiation and gene expression. They additionally provide an alternative molecular explanation for the inflammatory phenotype of Cpdm mice and the absence of disease transfer by hematopoetic stem cell transplantation. Unsorted bone marrow cells from wildtype and Cpdm mice were cultured for 10 days in the presence of ascorbic acid and ß-glycerophosphate to induce osteogenic differentiation
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