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      Vesicular Trafficking and Signaling for Cytokine and Chemokine Secretion in Mast Cells

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          Abstract

          Upon activation mast cells (MCs) secrete numerous inflammatory compounds stored in their cytoplasmic secretory granules by a process called anaphylactic degranulation, which is responsible for type I hypersensitivity responses. Prestored mediators include histamine and MC proteases but also some cytokines and growth factors making them available within minutes for a maximal biological effect. Degranulation is followed by the de novo synthesis of lipid mediators such as prostaglandins and leukotrienes as well as a vast array of cytokines, chemokines, and growth factors, which are responsible for late phase inflammatory responses. While lipid mediators diffuse freely out of the cell through lipid bilayers, both anaphylactic degranulation and secretion of cytokines, chemokines, and growth factors depends on highly regulated vesicular trafficking steps that occur along the secretory pathway starting with the translocation of proteins to the endoplasmic reticulum. Vesicular trafficking in MCs also intersects with endocytic routes, notably to form specialized cytoplasmic granules called secretory lysosomes. Some of the mediators like histamine reach granules via specific vesicular monoamine transporters directly from the cytoplasm. In this review, we try to summarize the available data on granule biogenesis and signaling events that coordinate the complex steps that lead to the release of the inflammatory mediators from the various vesicular carriers in MCs.

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          Most cited references152

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          Membrane fusion: grappling with SNARE and SM proteins.

          The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion. Vesicular and target membrane-localized SNARE proteins zipper up into an alpha-helical bundle that pulls the two membranes tightly together to exert the force required for fusion. SM proteins, shaped like clasps, bind to trans-SNARE complexes to direct their fusogenic action. Individual fusion reactions are executed by distinct combinations of SNARE and SM proteins to ensure specificity, and are controlled by regulators that embed the SM-SNARE fusion machinery into a physiological context. This regulation is spectacularly apparent in the exquisite speed and precision of synaptic exocytosis, where synaptotagmin (the calcium-ion sensor for fusion) cooperates with complexin (the clamp activator) to control the precisely timed release of neurotransmitters that initiates synaptic transmission and underlies brain function.
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            The development of allergic inflammation.

            Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.
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              Molecular mechanisms of translational control

              Key Points Translational regulation can be global or mRNA specific, and most examples of translational regulation that have been described so far affect the rate-limiting initiation step. Global control of translation is frequently exerted by regulating the phosphorylation or availability of initiation factors. Two of the most well-known examples are the regulation of eukaryotic initiation factor (eIF)4E availability by 4E-binding proteins (4E-BPs), and the modulation of the levels of active ternary complex by eIF2α phosphorylation. mRNA-specific translational control is driven by RNA sequences and/or structures that are commonly located in the untranslated regions of the transcript. These features are usually recognized by regulatory proteins or micro RNAs (miRNAs). Quasi-circularization of mRNAs can be mediated by the cap structure and the poly(A) tail via the eIF4E–eIF4G–polyA-binding-protein (PABP) interaction. Such interactions between the 5′ and the 3′ ends of mRNAs could provide a spatial framework for the action of regulatory factors that bind to the 3′ untranslated region (UTR). However, other forms of 5′–3′-end interactions are likely to occur as well. Many regulatory proteins target the stable association of the small ribosomal subunit with the mRNA. These factors function by steric hindrance (for example, iron-regulatory protein; IRP), by interfering with the eIF4F complex (for example, Maskin, Bicoid, Cup) or by as-yet-unknown, distinct mechanisms to control translation initiation (sex-lethal; SXL). Other regulatory molecules modulate the joining of the large ribosomal subunit (hnRNP K and E1) or, potentially, post-initiation translation steps (miRNAs). General translation factors can regulate the expression of specific mRNAs. An illustrative example is the stimulation of translation of the mRNA that encodes the GCN4 transcriptional activator by eIF2α phosphorylation.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/25027
                URI : http://frontiersin.org/people/u/181885
                URI : http://frontiersin.org/people/u/183428
                URI : http://frontiersin.org/people/u/183557
                URI : http://frontiersin.org/people/u/173465
                URI : http://frontiersin.org/people/u/183455
                URI : http://frontiersin.org/people/u/183453
                URI : http://frontiersin.org/people/u/183454
                URI : http://frontiersin.org/people/u/166452
                URI : http://frontiersin.org/people/u/4042
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                22 September 2014
                2014
                : 5
                : 453
                Affiliations
                [1] 1INSERM UMRS 1149 , Paris, France
                [2] 2CNRS ERL8252 , Paris, France
                [3] 3Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d’excellence INFLAMEX , Paris, France
                [4] 4Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , México City, México
                [5] 5Departamento de Farmacobiología, Cinvestav , México City, México
                Author notes

                Edited by: Paige Lacy, University of Alberta, Canada

                Reviewed by: Philippe Georgel, Strasbourg University, France; Jaya Talreja, Wayne State University, USA

                *Correspondence: Ulrich Blank, INSERM UMRS1149, Université Paris-Diderot, Faculté de Médecine Site X. Bichat, 16 rue Henri Huchard, Paris 75018, France e-mail: ulrich.blank@ 123456inserm.fr ; Claudia González-Espinosa, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Calzada de los Tenorios 235, Colonia Granjas Coapa, 14330 México City, México e-mail: cgonzal@ 123456cinvestav.mx

                Present address: Neeraj Tiwari, Department of Cell Biology, Yale University, New Haven, CT, USA

                This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2014.00453
                4170139
                25295038
                0507fa6d-2009-40e7-bfa9-d0cf76a91092
                Copyright © 2014 Blank, Madera-Salcedo, Danelli, Claver, Tiwari, Sánchez-Miranda, Vázquez-Victorio, Ramírez-Valadez, Macias-Silva and González-Espinosa.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 August 2014
                : 05 September 2014
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 193, Pages: 18, Words: 16356
                Categories
                Immunology
                Review Article

                Immunology
                mast cells,signaling,vesicular trafficking,secretion,inflammation
                Immunology
                mast cells, signaling, vesicular trafficking, secretion, inflammation

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