A dileucine signal situated in the C-terminal tail of the lysosomal membrane protein p40 is responsible for its targeting to lysosomes

International audienceTransport of newly synthesised lysosomal membrane proteins from the TGN to the lysosomes is due to the presence of specific signals in their cytoplasmic domains that are recognised by cytosolic adaptors. p40, a hypothetical transporter of 372 amino acids localised in the lysosomal membrane, contains four putative lysosomal sorting motifs in its sequence: three of the YXXΦ–type (Y6QLF, Y106VAL, Y333NGL) and one of the [D/E]XXXL[L/I]-type (EQERL360L361). To test the implication of these motifs in the biosynthetic transport of p40, we replaced the most critical residues of these consensus sequences, the tyrosine or the leucine-leucine pair, by alanine or alanine-valine, respectively. We analysed the subcellular localisation of the mutated p40 proteins in transfected HeLa cells by confocal microscopy and by biochemical approaches (subcellular fractionation on self-forming Percoll density gradients and cell surface biotinylation). Our results show that p40 is mis-targeted to the plasma membrane when its dileucine motif is disrupted. No role of the tyrosine motifs could be put forward. Taken together, our results provide evidence that the sorting of p40 from the TGN to the lysosomes is directed by the dileucine EQERL360L361 motif situated in its C-terminal tail

Responsabilité, risques et progrès :quelques enjeux récents du droit de la réparation des dommages

Six dispositions dans un (ancien) code civil et quelques lois particulières, oscillant entre faute et risque, voilà ce qui forme aujourd'hui notre droit de la responsabilité civile extracontractuelle. L'évolution de nos modes de consommation et les progrès scientifiques et technologiques mettent d'évidence à l'épreuve cet arsenal législatif tout à la fois dispersé, peu explicite et, à certains égards, peu préparé à accueillir de telles avancées. Le présent ouvrage s'arrête sur quelques-uns des enjeux actuels auxquels ce cadre législatif doit et devra répondre dans les domaines de l'environnement, des technologies numériques et des progrès pharmaceutiques.info:eu-repo/semantics/publishe

Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis

Introduction: Microscopic bowel inflammation is present in up to 50% of patients with spondyloarthritis (SpA) and is associated with more severe disease. Currently no reliable biomarkers exist to identify patients at risk. Calprotectin is a sensitive marker of neutrophilic inflammation, measurable in serum and stool. Objectives: To assess whether serum and faecal calprotectin in addition to C-reactive protein (CRP) can be used to identify patients with SpA at risk of microscopic bowel inflammation. Methods: Serum calprotectin and CRP were measured in 125 patients with SpA. In 44 of these patients, faecal samples were available for calprotectin measurement. All 125 patients underwent an ileocolonoscopy to assess the presence of microscopic bowel inflammation. Results: Microscopic bowel inflammation was present in 53 (42.4%) patients with SpA. Elevated serum calprotectin and CRP were independently associated with microscopic bowel inflammation. Faecal calprotectin was also significantly higher in patients with microscopic bowel inflammation. Patients with CRP and serum calprotectin elevated had a frequency of bowel inflammation of 64% vs 25% in patients with low levels of both. When either CRP or serum calprotectin was elevated, the risk was intermediate (40%) and measuring faecal calprotectin provided further differentiation. Hence we suggest a screening approach where initially serum calprotectin and CRP are assessed and, if necessary, faecal calprotectin. The model using this scenario provided an area under the ROC curve of 74.4% for detection of bowel inflammation. Conclusions: Calprotectin measurements in stool and serum, in addition to CRP, may provide a promising strategy to identify patients with SpA at risk of bowel inflammation and could play a role in overall patient stratification