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1.
Sci Immunol ; 9(92): eadi9769, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38207055

RESUMO

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Receptor 7 Toll-Like , Camundongos , Animais , Humanos , Receptor 7 Toll-Like/genética , Autoimunidade/genética , Receptor Toll-Like 9/metabolismo , Receptor 8 Toll-Like , Receptor 3 Toll-Like/metabolismo , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana Transportadoras
2.
Dev Biol ; 368(1): 44-53, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22641013

RESUMO

Invertebrates express a multitude of Wnt ligands and all Wnt/ß-catenin signaling pathways converge to only one nuclear Lef/Tcf. In vertebrates, however, four distinct Lef/Tcfs, i.e. Tcf-1, Lef, Tcf-3, and Tcf-4 fulfill this function. At present, it is largely unknown to what extent the various Lef/Tcfs are functionally similar or diversified in vertebrates. In particular, it is not known which domains are responsible for the Tcf subtype specific functions. We investigated the conserved and non-conserved functions of the various Tcfs by using Xenopus laevis as a model organism and testing Tcfs from Hydra magnipapillata, Caenorhabditis elegans and Drosophila melanogaster. In order to identify domains relevant for the individual properties we created series of chimeric constructs consisting of parts of XTcf-3, XTcf-1 and HyTcf. Rescue experiments in Xenopus morphants revealed that the three invertebrate Tcfs tested compensated the loss of distinct Xenopus Tcfs: Drosophila Tcf (Pangolin) can substitute for the loss of XTcf-1, XTcf-3 and XTcf-4. By comparison, Caenorhabditis Tcf (Pop-1) and Hydra Tcf (HyTcf) can substitute for the loss of only XTcf-3 and XTcf-4, respectively. The domain, which is responsible for subtype specific functions is the regulatory CRD domain. A phylogenetic analysis separates Tcf-1/Lef-1 from the sister group Tcf-3/4 in the vertebrate lineage. We propose that the vertebrate specific diversification of Tcfs in vertebrates resulted in subfunctionalization of a Tcf that already united most of the Lef/Tcf functions.


Assuntos
Fator 1 de Ligação ao Facilitador Linfoide/genética , Fatores de Transcrição TCF/genética , Vertebrados/genética , Proteínas de Xenopus/genética , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , DNA Antissenso/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Hydra/genética , Hydra/metabolismo , Hibridização In Situ , Fator 1 de Ligação ao Facilitador Linfoide/classificação , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Dados de Sequência Molecular , Filogenia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Fatores de Transcrição TCF/classificação , Fatores de Transcrição TCF/metabolismo , Fator 3 de Transcrição/genética , Fator 3 de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vertebrados/classificação , Vertebrados/metabolismo , Proteínas de Xenopus/classificação , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/genética , Xenopus laevis/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
3.
Bioresour Technol ; 118: 289-95, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22705536

RESUMO

In this study, the focus is on magnetic separation of fresh water algae Chlamydomonas reinhardtii and Chlorella vulgaris as well as marine algae Phaeodactylum tricornutum and Nannochloropsis salina by means of silica-coated magnetic particles. Due to their small size and low biomass concentrations, harvesting algae by conventional methods is often inefficient and cost-consuming. Magnetic separation is a powerful tool to capture algae by adsorption to submicron-sized magnetic particles. Hereby, separation efficiency depends on parameters such as particle concentration, pH and medium composition. Separation efficiencies of >95% were obtained for all algae while maximum particle loads of 30 and 77 g/g were measured for C. reinhardtii and P. tricornutum at pH 8 and 12, respectively. This study highlights the potential of silica-coated magnetic particles for the removal of fresh water and marine algae by high gradient magnetic filtration and provides critical discussion on future improvements.


Assuntos
Organismos Aquáticos/isolamento & purificação , Eucariotos/isolamento & purificação , Filtração/métodos , Água Doce , Magnetismo/métodos , Água do Mar , Adsorção , Organismos Aquáticos/citologia , Eucariotos/citologia , Eletricidade Estática , Temperatura
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