Niso-Santano M.,French Institute of Health and Medical Research |
Niso-Santano M.,University of Paris Descartes |
Niso-Santano M.,University Pierre and Marie Curie |
Pedro J.M.B.-S.,French Institute of Health and Medical Research |
And 21 more authors.
Autophagy | Year: 2015
The induction of autophagy usually requires the activation of PIK3C3/ VPS34 (phosphatidylinositol 3-kinase, catalytic subunit type 3) within a multiprotein complex that contains BECN1 (Beclin 1, autophagy related). PIK3C3 catalyzes the conversion of phosphatidylinositol into phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns3P associates with growing phagophores, which recruit components of the autophagic machinery, including the lipidated form of MAP1LC3B/LC3 (microtubule-associated protein 1 light chain 3 b). Depletion of BECN1, PIK3C3 or some of their interactors suppresses the formation of MAP1LC3B+ phagophores or autophagosomes elicited by most physiological stimuli, including saturated fatty acids. We observed that cis-unsaturated fatty acids stimulate the generation of cytosolic puncta containing lipidated MAP1LC3B as well as the autophagic turnover of long-lived proteins in the absence of PtdIns3P accumulation. In line with this notion, cis-unsaturated fatty acids require neither BECN1 nor PIK3C3 to stimulate the autophagic flux. Such a BECN1-independent autophagic response is phylogenetically conserved, manifesting in yeast, nematodes, mice and human cells. Importantly, MAP1LC3B+ puncta elicited by cisunsaturated fatty acids colocalize with Golgi apparatus markers. Moreover, the structural and functional collapse of the Golgi apparatus induced by brefeldin A inhibits cis-unsaturated fatty acid-triggered autophagy. It is tempting to speculate that the well-established healthpromoting effects of cis-unsaturated fatty acids are linked to their unusual capacity to stimulate noncanonical, BECN1-independent autophagic responses. © 2015, Taylor & Francis Group, LLC.
Coureuil M.,Institute Necker Enfants Malades |
Coureuil M.,University of Paris Descartes |
Coureuil M.,French Institute of Health and Medical Research |
Coureuil M.,French National Center for Scientific Research |
And 12 more authors.
Trends in Molecular Medicine | Year: 2014
Neisseria meningitidis is an extracellular pathogen, which, once in the bloodstream, has the ability to form microcolonies on the apical surface of endothelia. Pathogen interaction with microvessels is mediated by bacterial type IV pili and two receptors on endothelial cells: CD147 and the β2-adrenoceptor. CD147 facilitates the adhesion of diplococci to the endothelium, whereas the β2-adrenoceptor facilitates cell signaling, and crossing of the blood-brain barrier. In this review, we discuss how meningococcal interaction with endothelial cells is responsible for the specific clinical features of invasive meningococcal infection such as meningitis, and a peripheral thrombotic/vascular leakage syndrome possibly leading to purpura fulminans. © 2014 Elsevier Ltd.
Korniotis S.,Institute Necker Enfants Malades |
Korniotis S.,University of Paris Descartes |
Gras C.,Institute Necker Enfants Malades |
Gras C.,University of Paris Descartes |
And 16 more authors.
Nature Communications | Year: 2016
The influence of signals perceived by immature B cells during their development in bone marrow on their subsequent functions as mature cells are poorly defined. Here, we show that bone marrow cells transiently stimulated in vivo or in vitro through the Toll-like receptor 9 generate proB cells (CpG-proBs) that interrupt experimental autoimmune encephalomyelitis (EAE) when transferred at the onset of clinical symptoms. Protection requires differentiation of CpG-proBs into mature B cells that home to reactive lymph nodes, where they trap T cells by releasing the CCR7 ligand, CCL19, and to inflamed central nervous system, where they locally limit immunopathogenesis through interleukin-10 production, thereby cooperatively inhibiting ongoing EAE. These data demonstrate that a transient inflammation at the environment, where proB cells develop, is sufficient to confer regulatory functions onto their mature B-cell progeny. In addition, these properties of CpG-proBs open interesting perspectives for cell therapy of autoimmune diseases.
Liang N.,Institute Necker Enfants Malades |
Liang N.,French Institute of Health and Medical Research |
Liang N.,University of Paris Descartes |
Zhang C.,Institute Necker Enfants Malades |
And 34 more authors.
Journal of Experimental Medicine | Year: 2014
Genetic studies have shown that the tuberous sclerosis complex (TSC) 1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity. © 2014 Liang et al.
Sebti S.,Institute Of Recherche En Cancerologie Of Montpellier |
Sebti S.,French Institute of Health and Medical Research |
Sebti S.,Montpellier University |
Sebti S.,Institute Regional du Cancer Montpellier |
And 42 more authors.
Autophagy | Year: 2014
We recently reported that BAG6/BAT3 (BCL2-associated athanogene 6) is essential for basal and starvation-induced autophagy in E18.5 bag6-/- mouse embryos and in mouse embryonic fibroblasts (MEFs) through the modulation of the EP300/p300-dependent acetylation of TRP53 and autophagy-related (ATG) proteins. We observed that BAG6 increases TRP53 acetylation during starvation and pro-autophagic TRP53-target gene expression. BAG6 also decreases the EP300 dependent-acetylation of ATG5, ATG7, and LC3-I, posttranslational modifications that inhibit autophagy. In addition, in the absence of BAG6 or when using a mutant of BAG6 exclusively located in the cytoplasm, autophagy is inhibited, ATG7 is hyperacetylated, TRP53 acetylation is abrogated, and EP300 accumulates in the cytoplasm indicating that BAG6 is involved in the regulation of the nuclear localization of EP300. We also reported that the interaction between BAG6 and EP300 occurs in the cytoplasm rather than the nucleus. Moreover, during starvation, EP300 is transported to the nucleus in a BAG6-dependent manner. We concluded that BAG6 regulates autophagy by controlling the localization of EP300 and its accessibility to nuclear (TRP53) and cytoplasmic (ATGs) substrates. © 2014 Landes Bioscience.