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MARCH1 protects the lipid raft and tetraspanin web from MHCII proteotoxicity in dendritic cells

Dendritic cells (DCs) produce major histocompatibility complex II (MHCII) in large amounts to function as professional antigen presenting cells. Paradoxically, DCs also ubiquitinate and degrade MHCII in a constitutive manner. Mice deficient in the MHCII-ubiquitinating enzyme membrane-anchored RING-CH1, or the ubiquitin-acceptor lysine of MHCII, exhibit a substantial reduction in the number of regulatory T (Treg) cells, but the underlying mechanism was unclear. Here we report that ubiquitin-dependent MHCII turnover is critical to maintain homeostasis of lipid rafts and the tetraspanin web in DCs. Lack of MHCII ubiquitination results in the accumulation of excessive quantities of MHCII in the plasma membrane, and the resulting disruption to lipid rafts and the tetraspanin web leads to significant impairment in the ability of DCs to engage and activate thymocytes for Treg cell differentiation. Thus, ubiquitin-dependent MHCII turnover represents a novel quality-control mechanism by which DCs maintain homeostasis of membrane domains that support DC's Treg cell-selecting function

The Discovery of the Koryaks and Their Perception of the World

The first information that we have about the Koryaks was reported in 1669 by Sosnovskij, the administrator of the small fortified town of Okhotsk, who had heard of them from the Tunguzian people. The first true ethnographic data were gathered only in 1700, when Atlasov (1935 [1891)], who had left the fortified town of Anadyr in 1697 to explore new territory, discovered Kamchatka and collected interesting information about the population of that peninsula, in particular the Koryaks. This was the beginning of a long period of exposure. Without doubt, it was the 'second Kamchatka expedition' (1733-1746) that supplied the most useful elements of the study for this region and its population. ..

Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

Distinct Regions of the Large Extracellular Domain of Tetraspanin CD9 Are Involved in the Control of Human Multinucleated Giant Cell Formation

Multinucleated giant cells, formed by the fusion of monocytes/macrophages, are features of chronic granulomatous inflammation associated with infections or the persistent presence of foreign material. The tetraspanins CD9 and CD81 regulate multinucleated giant cell formation: soluble recombinant proteins corresponding to the large extracellular domain (EC2) of human but not mouse CD9 can inhibit multinucleated giant cell formation, whereas human CD81 EC2 can antagonise this effect. Tetraspanin EC2 are all likely to have a conserved three helix sub-domain and a much less well-conserved or hypervariable sub-domain formed by short helices and interconnecting loops stabilised by two or more disulfide bridges. Using CD9/CD81 EC2 chimeras and point mutants we have mapped the specific regions of the CD9 EC2 involved in multinucleated giant cell formation. These were primarily located in two helices, one in each sub-domain. The cysteine residues involved in the formation of the disulfide bridges in CD9 EC2 were all essential for inhibitory activity but a conserved glycine residue in the tetraspanin-defining ‘CCG’ motif was not. A tyrosine residue in one of the active regions that is not conserved between human and mouse CD9 EC2, predicted to be solvent-exposed, was found to be only peripherally involved in this activity. We have defined two spatially-distinct sites on the CD9 EC2 that are required for inhibitory activity. Agents that target these sites could have therapeutic applications in diseases in which multinucleated giant cells play a pathogenic role

R-spondin1 regulates muscle progenitor cell differentiation and fusion through dual regulation of canonical and non-canonical Wnt signaling pathways

Orchestration of numerous molecular pathways is required to deliver stem cells mediated tissue regeneration. As such, mechanisms controlling one aspect of regeneration are often antagonistic to others. Much attention has focused on Wntmediated signalings as this family is involved in many important steps in mammalian regeneration. In many cell types, the R-spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that Rspo1-null muscles do not display any abnormalities at the basal level. However deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle progenitor cells lacking Rspo1 show delayed differentiation. Transcriptome analysis demonstrated that Rspo1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking Rspo1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of canonical and non-canonical Wnt signaling pathways by Rspo1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage

Tetraspanin CD9 limits mucosal healing in experimental colitis

Tetraspanins are a family of proteins with four transmembrane domains that associate between themselves and cluster with other partner proteins, conforming a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs). These TEMs constitute macromolecular signaling platforms that regulate key processes in several cellular settings controlling signaling thresholds and avidity of receptors. In this study, we investigated the role of CD9, a tetraspanin that regulates major biological processes such as cell migration and immunological responses, in two mouse models of colitis that have been used to study the pathogenesis of inflammatory bowel disease (IBD). Previous in vitro studies revealed an important role in the interaction of leukocytes with inflamed endothelium, but in vivo evidence of the involvement of CD9 in inflammatory diseases is scarce. Here, we studied the role of CD9 in the pathogenesis of colitis in vivo. Colitis was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen that causes epithelial disruption and intestinal inflammation. CD9 -/- mice showed less severe colitis than wild-type counterparts upon exposure to DSS (2% solution) and enhanced survival in response to a lethal DSS dose (4%). Decreased neutrophil and macrophage cell infiltration was observed in colonic tissue from CD9 -/- animals, in accordance with their lower serum levels of TNF-α, IL-6, and other proinflammatory cytokines in the colon. The specific role of CD9 in IBD was further dissected by transfer of CD4 + CD45RB hi naive T cells into the Rag1 -/- mouse colitis model. However, no significant differences were observed in these settings between both groups, ruling out a role for CD9 in IBD in the lymphoid compartment. Experiments with bone marrow chimeras revealed that CD9 in the non-hematopoietic compartment is involved in colon injury and limits the proliferation of epithelial cells. Our data indicate that CD9 in non-hematopoietic cells plays an important role in colitis by limiting epithelial cell proliferation. Future strategies to repress CD9 expression may be of therapeutic benefit in the treatment of IBDThis work was supported by grants to FS-M (SAF2014-55579-R; INDISNET-S2011/BMD-2332; ERC-2011-AdG 294340-GENTRIS; PIE13/00041; and CIBER CARDIOVASCULAR) and was cofunded by Fondo Europeo de Desarrollo Regional (FEDER). The CNIC is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and by the Pro CNIC Foundatio

Les Français du Québec et leur(s) insécurité(s) : linguistique, identitaire et/ou culturelle?

La migration, rencontre interculturelle, impose une confrontation à de nouvelles références culturelles et langagières. Les choix langagiers d’un immigrant français au Québec ont pour objet soit un souci d’intégration, la volonté de se faire juger favorablement par les acteurs de la société d’accueil, soit la perspective d’une rentabilisation de leurs biens linguistiques, misant sur la culture « à la française » pour augmenter leur capital. Cette étude exploratoire vise à observer de plus près les différents éléments linguistiques, identitaires et culturels que les immigrants français de l’Estrie se disent prêts à modifier, si ces modifications peuvent les insécuriser et si cette insécurité peut être à l’origine d’un projet migratoire jugé insatisfaisant. L’analyse de leurs discours métalinguistiques autobiographiques révèle le rôle des différentes variétés de langue dans les processus de sécurisation ou d’insécurisation linguistique et identitaire. Construits autour de normes identitaires très fortes, ces immigrants font fi des jugements de la société québécoise. Leur sujétion à la culture française, au capital symbolique irremplaçable, les place dans une position de sécurité linguistique, identitaire et culturelle. Cette position reste toutefois instable chez les locuteurs témoignant d’une prédisposition à l’insécurité linguistique, ainsi que chez ceux affichant une insécurité identitaire, liée aux déconstructions et reconstructions identitaires inhérentes au parcours migratoire