Pathways of integrins in the endo-lysosomal system

In this review, we present recent scientific advances about integrin trafficking in the endo-lysosomal system. In the last few years, plenty of new information has emerged about the endo-lysosomal system, integrins, and the mechanism, how exactly the intracellular trafficking of integrins is regulated. We review the internalization and recycling pathways of integrins, and we provide information about the possible ways of lysosomal degradation through the endosomal and autophagic system. The regulation of integrin internalization and recycling proved to be a complex process worth studying. Trafficking of integrins, together with the regulation of their gene expression, defines cellular adhesion and cellular migration through bidirectional signalization and ligand binding. Thus, any malfunction in this system can potentially (but not necessarily) lead to tumorigenesis or metastasis. Hence, extensive examinations of integrins in the endo-lysosomal system raise the possibility to identify potential new medical targets. Furthermore, this knowledge can also serve as a basis for further determination of integrin signaling- and adhesion-related processes

A gluten-enteropathia kialakulását befolyásoló tényezők vizsgálata = Factors influencing the development of coeliac disease

Kutatásunk során új hajlamosító géneket írtunk le, melyet közrejátszhatnak a gluten-enteropathia (coeliakia) kialakulásában, ezek befolyásolják a T lymphocyták érését és kollaborációját a B sejtekkel, a toll-like receptorokat és a gyulladás során termelődő cytokineket. Megállapítottuk, hogy a coeliakia kialakulása és klinikai megjelenése asszociációt mutat a haptoglobin polimorfizmussal is, melyről a mi közlésünket követően független kutatók igazolták, hogy egyik altípusa azonos vékonybél permeabilitásában kulcsszerepet játszó zonulin molekulával. A kutatás során azonosítottuk a coeliakia-specifikus autoantitestek fő kötőhelyét az autoantigén, a 2-es típusú transzglutamináz enzim felszínén. Megállapítottuk, hogy a coeliakia antitestek betegség-specifikusan ugyanazt a komplex, háromdimenziós epitópot ismerik fel. Sejtkultúrában a coeliakia antitestek gátolják az erek képződését és fokozzák azok permeabilitását, elsősorban a RhoA túlzott aktiválásán keresztül. Megszerveztük és elvégeztük az első reprezentatív coeliakia szűrővizsgálatot Magyarországon. Megállapítottuk, hogy a coeliakia hazai előfordulása 1.3% körül van a magyar gyermekek és fiatal felnőttek körében. A szűrővizsgálatokra egyszerű, helyszíni antitest kimutatáson alapuló szűrő eljárást validáltunk. Kimutattuk, hogy a klinikailag fel nem ismert coeliakia kedvezőtlenül befolyásolja a hepatitis védőoltásra adott immunválaszt és az antitestek szerepet játszanak idegrendszeri szövődmény (ataxia) kialakulásában. | This research identified new susceptibility genes for coeliac disease, a common autoimmune enteropathy triggered by gluten peptides ingested with dietary cereals. The novel genes are mostly related to T-lymphocyte development, collaboration of T and B cells, toll-like receptors and cytokines. We also described association with haptoglobin polymorphism, a master regulator of intestinal permeability also known as zonulin. Predisposing alleles of these genes create a more inflammatory environment in the gut and in multiple copies confer additional risk to HLA-DQ alleles. We identified the main binding epitope of coeliac disease anti-transglutaminase 2 autoantibodies. This epitope has a complex, three-dimensional structure and is disease-specific. Patient antibodies targeting this epitope enhance the enzymatic activity of transglutaminase 2 and cause disturbances in the angiogenesis and vascular permeability in cell culture models via the inappropriate activation of RhoA. We performed the first representative population screening for coeliac disease in Hungary and established that the prevalence is around 1.3% in both children and young adults. The methodology of the screening has been advanced by the application of rapid, onsite antibody detection. Unrecognised coeliac disease was found to predispose to a defective immune response to hepatitis B vaccination (reversible after treatment) and we showed the contribution of coeliac disease antibodies in the late neural complications

On the Fly: Recent Progress on Autophagy and Aging in Drosophila

Autophagy ensures the lysosome-mediated breakdown and recycling of self-material, as it not only degrades obsolete or damaged intracellular constituents but also provides building blocks for biosynthetic and energy producing reactions. Studies in animal models including Drosophila revealed that autophagy defects lead to the rapid decline of neuromuscular function, neurodegeneration, sensitivity to stress (such as starvation or oxidative damage), and stem cell loss. Of note, recently identified human Atg gene mutations cause similar symptoms including ataxia and mental retardation. Physiologically, autophagic degradation (flux) is known to decrease during aging, and this defect likely contributes to the development of such age-associated diseases. Many manipulations that extend lifespan (including dietary restriction, reduced TOR kinase signaling, exercise or treatment with various anti-aging substances) require autophagy for their beneficial effect on longevity, pointing to the key role of this housekeeping process. Importantly, genetic (e.g., Atg8a overexpression in either neurons or muscle) or pharmacological (e.g., feeding rapamycin or spermidine to animals) promotion of autophagy has been successfully used to extend lifespan in Drosophila, suggesting that this intracellular degradation pathway can rejuvenate cells and organisms. In this review, we highlight key discoveries and recent progress in understanding the relationship of autophagy and aging in Drosophila

Ion Channels and Pumps in Autophagy: A Reciprocal Relationship

Autophagy, the process of cellular self-degradation, is intrinsically tied to the degradative function of the lysosome. Several diseases have been linked to lysosomal degradative defects, including rare lysosomal storage disorders and neurodegenerative diseases. Ion channels and pumps play a major regulatory role in autophagy. Importantly, calcium signaling produced by TRPML1 (transient receptor potential cation channel, mucolipin subfamily) has been shown to regulate autophagic progression through biogenesis of autophagic-lysosomal organelles, activation of mTORC1 (mechanistic target of rapamycin complex 1) and degradation of autophagic cargo. ER calcium channels such as IP(3)Rs supply calcium for the lysosome, and lysosomal function is severely disrupted in the absence of lysosomal calcium replenishment by the ER. TRPML1 function is also regulated by LC3 (microtubule-associated protein light chain 3) and mTORC1, two critical components of the autophagic network. Here we provide an overview of the current knowledge about ion channels and pumps—including lysosomal V-ATPase (vacuolar proton-ATPase), which is required for acidification and hence proper enzymatic activity of lysosomal hydrolases—in the regulation of autophagy, and discuss how functional impairment of some of these leads to diseases

MiniCORVET is a Vps8-containing hemocyte- and nephrocyte-specific early endosomal tether in Drosophila

Cet ouvrage est la version « allégée », mais substantielle, d’une thèse de doctorat soutenue le 9 novembre 2009 à l’Université de Nice Sophia Antipolis. Disons d’emblée que cette étude, très structurée et écrite dans une langue limpide, est remarquable et devra être lue et méditée par les historiens de la justice. Ils y trouveront un modèle d’analyse dialectique des rapports entre délinquance et fonctionnement des institutions pénales replacées dans leur contexte législatif et historique. S’i..

Rhodolith Beds Are Major CaCO3 Bio-Factories in the Tropical South West Atlantic

Rhodoliths are nodules of non-geniculate coralline algae that occur in shallow waters (<150 m depth) subjected to episodic disturbance. Rhodolith beds stand with kelp beds, seagrass meadows, and coralline algal reefs as one of the world's four largest macrophyte-dominated benthic communities. Geographic distribution of rhodolith beds is discontinuous, with large concentrations off Japan, Australia and the Gulf of California, as well as in the Mediterranean, North Atlantic, eastern Caribbean and Brazil. Although there are major gaps in terms of seabed habitat mapping, the largest rhodolith beds are purported to occur off Brazil, where these communities are recorded across a wide latitudinal range (2°N - 27°S). To quantify their extent, we carried out an inter-reefal seabed habitat survey on the Abrolhos Shelf (16°50′ - 19°45′S) off eastern Brazil, and confirmed the most expansive and contiguous rhodolith bed in the world, covering about 20,900 km2. Distribution, extent, composition and structure of this bed were assessed with side scan sonar, remotely operated vehicles, and SCUBA. The mean rate of CaCO3 production was estimated from in situ growth assays at 1.07 kg m−2 yr−1, with a total production rate of 0.025 Gt yr−1, comparable to those of the world's largest biogenic CaCO3 deposits. These gigantic rhodolith beds, of areal extent equivalent to the Great Barrier Reef, Australia, are a critical, yet poorly understood component of the tropical South Atlantic Ocean. Based on the relatively high vulnerability of coralline algae to ocean acidification, these beds are likely to experience a profound restructuring in the coming decades