Regulated mucin secretion from airway epithelial cells.
Regulated mucin secretion from airway epithelial cells.
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DOI：
10.3389/fendo.2013.00129
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发表时间：
2013-09-18
影响因子：
5.2
通讯作者：
Dickey BF
中科院分区：
文献类型：
--
作者：
Adler KB;Tuvim MJ;Dickey BF
近端气道的分泌上皮细胞合成并分泌形成凝胶的聚合粘蛋白。分泌的粘蛋白吸附水以形成粘液，所述粘液由邻近的纤毛细胞推动，提供移动的屏障，所述屏障将吸入的颗粒和病原体从肺部移除。粘蛋白的细胞内运输的几个特征使得气道分泌细胞成为调节胞吐作用的细胞生物学的一个有趣的比较物。聚合粘蛋白是非常大的分子（每个单体高达3 × 106 Da），其在ER中的折叠和初始聚合需要蛋白质二硫键异构酶Agr 2。在高尔基体中，粘蛋白进一步聚合形成链和可能的分支网络，包括超过20个单体。粘蛋白聚合物的大尺寸对其沿着分泌途径包装成运输囊泡施加限制。糖侧链占粘蛋白质量的>70%，并且它们通过O-糖基化与蛋白质核心的连接发生在高尔基体中。成熟的多聚粘蛋白储存在直径约1 μm的大分泌颗粒中。通过肉豆蔻酰化富含丙氨酸的C激酶底物、半胱氨酸串蛋白、热休克蛋白70和细胞骨架之间的协同相互作用，这些蛋白被转移到顶端膜，以定位用于胞吐。粘蛋白颗粒以低的基础速率和高的刺激速率与质膜进行胞吐融合。这两种速率都是由调节的胞吐机制介导的，如缺乏Munc 13 -2（第二信使钙和甘油二酯（DAG）的传感器）的小鼠的基础和刺激分泌中的表型所示。基础分泌是由以旁分泌方式释放的细胞外ATP及其代谢物腺苷对P2 Y2嘌呤能和A3腺苷受体的低水平激活诱导的。刺激的分泌是由高水平的相同配体诱导的，也可能是由炎症介质诱导的。活化的受体通过Gq与磷脂酶C偶联，导致DAG和从顶端ER释放钙的IP 3的产生。刺激分泌需要激活低亲和力钙传感器Synaptotagmin-2，而相应的高亲和力钙传感器在基础分泌是未知的。核心胞吐机制由SNARE蛋白VAMP 8、SNAP 23和未知的Syntaxin蛋白以及支架蛋白Munc 18 b组成。突出显示了与神经内分泌细胞和神经元相比，这种胞吐系统的共同和独特特征。
Secretory epithelial cells of the proximal airways synthesize and secrete gel-forming polymeric mucins. The secreted mucins adsorb water to form mucus that is propelled by neighboring ciliated cells, providing a mobile barrier which removes inhaled particles and pathogens from the lungs. Several features of the intracellular trafficking of mucins make the airway secretory cell an interesting comparator for the cell biology of regulated exocytosis. Polymeric mucins are exceedingly large molecules (up to 3 × 106 Da per monomer) whose folding and initial polymerization in the ER requires the protein disulfide isomerase Agr2. In the Golgi, mucins further polymerize to form chains and possibly branched networks comprising more than 20 monomers. The large size of mucin polymers imposes constraints on their packaging into transport vesicles along the secretory pathway. Sugar side chains account for >70% of the mass of mucins, and their attachment to the protein core by O-glycosylation occurs in the Golgi. Mature polymeric mucins are stored in large secretory granules ∼1 μm in diameter. These are translocated to the apical membrane to be positioned for exocytosis by cooperative interactions among myristoylated alanine-rich C kinase substrate, cysteine string protein, heat shock protein 70, and the cytoskeleton. Mucin granules undergo exocytic fusion with the plasma membrane at a low basal rate and a high stimulated rate. Both rates are mediated by a regulated exocytic mechanism as indicated by phenotypes in both basal and stimulated secretion in mice lacking Munc13-2, a sensor of the second messengers calcium and diacylglycerol (DAG). Basal secretion is induced by low levels of activation of P2Y2 purinergic and A3 adenosine receptors by extracellular ATP released in paracrine fashion and its metabolite adenosine. Stimulated secretion is induced by high levels of the same ligands, and possibly by inflammatory mediators as well. Activated receptors are coupled to phospholipase C by Gq, resulting in the generation of DAG and of IP3 that releases calcium from apical ER. Stimulated secretion requires activation of the low affinity calcium sensor Synaptotagmin-2, while a corresponding high affinity calcium sensor in basal secretion is not known. The core exocytic machinery is comprised of the SNARE proteins VAMP8, SNAP23, and an unknown Syntaxin protein, together with the scaffolding protein Munc18b. Common and distinct features of this exocytic system in comparison to neuroendocrine cells and neurons are highlighted.